Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia.

Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p.

Multidisciplinary Network ActiveOncoKids guidelines for providing movement and exercise in pediatric oncology: Consensus-based recommendations.

BACKGROUND: Pediatric cancer leads to reduced participation in exercise and only few patients comply with national physical activity recommendations. Physically inactive behavior hinders motor development and increases physical and psychological adverse effects of therapy and incidence of sequelae. Currently, there is neither nationwide coverage nor uniform level of knowledge regarding exercise promotion. The objective of the guideline is to facilitate qualified exercise interventions through standardized procedures in addition to regular physiotherapy and overall avoid physical inactivity in pediatric cancer patients. METHODS: This guideline addresses the multidisciplinary treatment team and informs physiotherapists and decision-makers in tertiary care hospitals and health insurance companies. The requirements of the Association of the Scientific Medical Societies in Germany were followed. Contents were based on best practice experience of experts, patient advocates, as well as on scientific evidence. RESULTS: The guideline includes 11 recommendations. Recommendations 1-4 declare the relevance of implementing exercise interventions and address general framework conditions. Recommendations 5-11 focus on the design of exercise programs, prevention and safety issues, relative contraindications for specific training loads, and options to overcome barriers to exercise. CONCLUSION: This guideline summarizes existing and established structures and evidence in the context of movement and exercise in pediatric oncology. It takes into consideration the rights, varying needs, and characteristics of children and adolescents as well as national and international experience in this field. In the future, relevant research gaps need to be addressed by high-quality intervention studies to provide the scientific background for a stronger evidence-based guideline.

Therapeutic Drug Monitoring of Asparaginase: Intra-individual Variability and Predictivity in Children With Acute Lymphoblastic Leukemia Treated With PEG-Asparaginase in the AIEOP-BFM Acute Lymphoblastic Leukemia 2009 Study.

BACKGROUND: Therapeutic drug monitoring (TDM) can identify patients with subtherapeutic asparaginase (ASNase) activity [silent inactivation (SI)] and prospectively guide therapeutic adaptation. However, limited intra-individual variability is a precondition for targeted dosing and the diagnosis of SI. METHODS: In the AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 trial, 2771 children with ALL were included and underwent ASNase-TDM in a central laboratory in Münster. Two biweekly administrations of pegylated ASNase during induction and a third dose during reinduction or the high-risk block, which was administered several weeks later, were monitored. We calculated (1) the incidence of SI; and (2) the predictivity of SI for SI after the subsequent administration. ASNase activities monitored during induction were categorized into percentiles at the respective sampling time points. These percentiles were used to calculate the intra-individual range of percentiles as a surrogate for intrapatient variability and to evaluate the predictivity of ASNase activity for the subsequent administration. RESULTS: The overall incidence of SI was low (4.9%). The positive predictive value of SI identified by one sample was ≤21%. Confirmation of SI by a second sample indicated a high positive predictive value of 100% for biweekly administrations, but not for administration more than 17 weeks later. Sampling and/or documentation errors were risks for misdiagnosis of SI. High intra-individual variability in ASNase activities, with ranges of percentiles over more than 2 quartiles and low predictivity, was observed in approximately 25% of the patients. These patients were likely to fail dose individualization based on TDM data. CONCLUSIONS: To use TDM as a basis for clinical decisions, standardized clinical procedures are required and high intra-individual variability should be taken into account. Details of the treatment are available in the European Clinical Trials Database at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004270-43/DE.

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study.

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 µmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 µmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 µmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.

Therapeutic Drug Monitoring of Asparaginase Activity-Method Comparison of MAAT and AHA Test Used in the International AIEOP-BFM ALL 2009 Trial.

BACKGROUND: In the international AIEOP-BFM ALL 2009 trial, asparaginase (ASE) activity was monitored after each dose of pegylated Escherichia coli ASE (PEG-ASE). Two methods were used: the aspartic acid ß-hydroxamate (AHA) test and medac asparaginase activity test (MAAT). As the latter method overestimates PEG-ASE activity because it calibrates using E. coli ASE, method comparison was performed using samples from the AIEOP-BFM ALL 2009 trial. METHODS: PEG-ASE activities were determined using MAAT and AHA test in 2 sets of samples (first set: 630 samples and second set: 91 samples). Bland-Altman analysis was performed on ratios between MAAT and AHA tests. The mean difference between both methods, limits of agreement, and 95% confidence intervals were calculated and compared for all samples and samples grouped according to the calibration ranges of the MAAT and the AHA test. RESULTS: PEG-ASE activity determined using the MAAT was significantly higher than when determined using the AHA test (P < 0.001; Wilcoxon signed-rank test). Within the calibration range of the MAAT (30-600 U/L), PEG-ASE activities determined using the MAAT were on average 23% higher than PEG-ASE activities determined using the AHA test. This complies with the mean difference reported in the MAAT manual. With PEG-ASE activities >600 U/L, the discrepancies between MAAT and AHA test increased. Above the calibration range of the MAAT (>600 U/L) and the AHA test (>1000 U/L), a mean difference of 42% was determined. Because more than 70% of samples had PEG-ASE activities >600 U/L and required additional sample dilution, an overall mean difference of 37% was calculated for all samples (37% for the first and 34% for the second set). CONCLUSIONS: Comparison of the MAAT and AHA test for PEG-ASE activity confirmed a mean difference of 23% between MAAT and AHA test for PEG-ASE activities between 30 and 600 U/L. The discrepancy increased in samples with >600 U/L PEG-ASE activity, which will be especially relevant when evaluating high PEG-ASE activities in relation to toxicity, efficacy, and population pharmacokinetics.

One in Four Questioned Children Faces Problems Regarding Reintegration Into Physical Education at School After Treatment for Pediatric Cancer.

Resumption of physical activity and reintegration into social surroundings after treatment for pediatric cancer is of high importance to recover from the burden of disease and treatment and to positively influence long-term health outcomes. Eighty-three children who had completed intensive treatment for pediatric cancer were surveyed regarding their participation in physical education at school (PES). The results show a concerning low rate of participation, particularly in children treated for pediatric bone tumors, and associated barriers. Reported reasons for quitting PES seem to be conquerable by individual and entity-related support to enable participation according to the children's desire.

Motor Performance After Treatment for Pediatric Bone Tumors.

BACKGROUND: Reduced motor performance can negatively affect physical activity and social partake after childhood cancer. Especially in bone tumor patients, who are at risk of physical limitations due to surgical interventions, motor performance has not yet been sufficiently investigated. Therefore, this study aimed at assessing motor performance in pediatric bone tumor patients. PROCEDURE: Motor performance was measured within 2 years posttreatment using the MOON (test for MOtor performance in pediatric ONcology) test. This instrument enables quantitative data collection even in physically impaired patients for comparison with age-matched and sex-matched reference values. RESULTS: Twenty-one patients (13 male) ages 15.2±2.1 years (median: 15 y, 10 to 19 y) and 9.4±7.4 months posttreatment (median: 6 mo, 2 to 24 mo) were tested. Motor performance was slightly reduced in muscular endurance of the legs; significantly reduced in speed, flexibility, eye-hand coordination, and muscular explosive strength (P<0.001), whereas patients' hand grip strength and static balance were superior to the reference values. Follow-up duration, body mass index, and tumor localization apparently affected motor performance. CONCLUSIONS: These findings show serious reductions in motor performance within 2 years after bone tumor treatment and highlight the need for interventions to improve motor performance. The results should be used to advise and support patients to engage in suitable physical and sports activities.

Motor performance in children and adolescents with cancer at the end of acute treatment phase.

UNLABELLED: Reduced motor performance may particularly limit reintegration into normal life after cessation of treatment in pediatric cancer patients. This study aimed at analyzing motor performance at the end of the acute treatment phase and reveals potential risk factors for motor deficits. A childhood cancer population with different tumor entities was assessed with the MOON test, which allows for comparison with age- and gender-matched reference values of healthy children, at the end of the acute treatment phase. Forty-seven patients were tested at 7.0 ± 2.6 months after diagnosis. Significant reductions of motor performance affected muscular explosive strength (P < 0.001), handgrip strength (P < 0.001), muscular endurance of legs (P = 0.035), hand-eye coordination (P < 0.001), static balance (P = 0.003), speed (P = 0.012), and flexibility (P < 0.001). Loss of upper extremity coordination did not achieve statistical significance. Associations between single motor deficits and the tumor entity, age, body mass index, and inactivity during treatment were revealed, whereas no associations were found for gender and vincristine application. CONCLUSION: Overall, motor performance was low in the patient group studied. We recommend that individualized exercise interventions to attenuate motor deficits and promote physical activity are needed during cancer treatment in order to enhance motor performance and improve social participation during and after cancer therapy.

The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia.

We prospectively studied the incidence and clinical course of hypertriglyceridemia and hypercholesterolemia during very prolonged use of asparaginase in relation to levels of asparaginase activity in children with acute lymphoblastic leukemia. We also evaluated the incidence of pancreatitis, thrombosis, hyperammonemia and central neurotoxicity and their association with asparaginase activity levels. Eighty-nine patients were treated according to the Dutch Childhood Oncology Group Acute Lymphoblastic Leukemia 10 medium-risk intensification protocol, which includes 15 doses of PEGasparaginase (2,500 IU/m(2)) over 30 weeks. Erwinia asparaginase (20,000 IU/m(2)) was administered when allergy to or silent inactivation of PEGasparaginase occurred. Triglyceride, cholesterol and ammonia levels increased rapidly in children treated with PEGasparaginase and remained temporarily elevated, but normalized after administration of the last asparaginase dose. Among the patients treated with PEGasparaginase, hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found in 47% and 25%, respectively. The correlation between PEGasparaginase activity levels and triglyceride levels was strongest at week 5 (Spearman correlation coefficient = 0.36, P = 0.005). The triglyceride levels were higher in children ≥ 10 years old than in younger patients (<10 years old) after adjustment for type of asparaginase preparation: median 4.9 mmol/L versus 1.6 mmol/L (P<0.001). In patients receiving Erwinia asparaginase, triglyceride levels increased in the first weeks as well, but no grade 3/4 dyslipidemia was found. Hyperammonemia (grade 3/4) was only found in patients treated with Erwinia asparaginase (9%). Thrombosis occurred in 4.5%, pancreatitis in 7%, and central neurotoxicity in 9% of patients using either of the two agents; these toxicities were not related to levels of asparaginase activity or to triglyceride levels. In conclusion, severe dyslipidemia occurred frequently, but was temporary and was not associated with relevant clinical events and should not, therefore, be considered a reason for modifying asparaginase treatment. Dyslipidemia was the only toxicity related to levels of asparaginase activity.

Immediate cooling does not prevent the ex vivo hydrolysis of L-asparagine by asparaginase.

BACKGROUND: Monitoring of asparagine (ASN) during asparaginase (ASE) treatment directly links to the antileukemic effect of ASE but is challenging because of ASE-induced ex vivo hydrolysis of ASN. Assuming that ASE is not active at 4°C, immediate cooling of blood samples became the accepted method for ASN determination during ASE therapy. METHODS: To evaluate the effect of immediate sample cooling on the ex vivo hydrolysis of ASN by ASE the degradation of C4-ASN in whole blood, spiked with different ASE concentrations were analyzed HPLC-MS. C4-ASN and ASE were added either to blood at 4°C or to blood at 37°C, which was instantly cooled down to 4°C. RESULTS: Immediate cooling did not prevent the ex vivo hydrolysis of ASN by ASE. The rate of ASN degradation to aspartic acid depended on the amount of ASE, ASE preparation, and time. Spiked into blood at 4°C 100 U/L native E. coli ASE already immediately degraded 100% of C4-ASN, whereas 10 U/L reduced the amount of C4-ASN by 30%. Spiked into blood at 37°C, which was immediately cooled thereafter, 10 U/L native E. coli ASE hydrolyzed 60% of C4-ASN and 1 U/L between 5% and 10% of C4-ASN. Concentrations of aspartic acid increased in parallel with ASN degradation. In addition, the ex vivo hydrolysis also affected concentrations of glutamine and glutamic acid. CONCLUSIONS: Cooling of blood samples did not inactivate ASE. Thus, to evaluate the precise pharmacodynamics of ASE, alternative methods for effective ASE inactivation at the time of blood withdrawal are needed.

Comparison of self-reported physical activity in children and adolescents before and during cancer treatment.

BACKGROUND: Physical activities are important for the development of children and increasing evidence suggests beneficial effects of physical activity promotion during cancer treatment as well. The present study aimed at evaluating the current need of exercise interventions in pediatric cancer patients undergoing acute treatment and identifying risk factors for inactivity. PROCEDURE: Data about self-reported physical activity before and during treatment was collected in a cross-sectional design with the physical activity questionnaire from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) in a modified cancer specific version. RESULTS: One hundred thirty pediatric cancer patients with various entities were questioned 3.0 ± 1.6 months since diagnosis. Patients' activity levels before diagnosis mainly matched reference values for healthy children in Germany. Reductions during treatment affected all dimensions of daily physical activities and minutes of exercise per week decreased significantly (P < 0.001). Largest reductions of physical activities during treatment were identified for bone tumor patients and in-patient stays. CONCLUSIONS: Due to the well known importance of physical activity during childhood and the identified risk of inactivity during cancer treatment, supervised exercise interventions should be implemented into acute treatment phase to enhance activity levels and ensure a continuously support by qualified exercise professionals.

Experience of barriers and motivations for physical activities and exercise during treatment of pediatric patients with cancer.

BACKGROUND: Due to growing evidence about the value of exercise in pediatric cancer patients, the purpose of this study was to determine factors that influence participation in physical activities and exercise in children and adolescents during treatment. PROCEDURE: This cross-sectional qualitative study included 40 pediatric cancer patients during intensive treatment. Patients were recruited at the Department for Pediatric Hematology and Oncology, University Hospital of Muenster where a supervised exercise program has been implemented for hospital stays. The qualitative approach included semi-structured guideline interviews, transcription and coding based on grounded theory. Four major topics were discussed in the interviews: (1) values and beliefs, (2) barriers to exercise, (3) motivations to exercise, and (4) encouragement from parents and physicians. RESULTS: Patients reported mainly positive attitudes toward physical activities during treatment and the local exercise program was desired and valued as essential for engaging in exercise during in-patient stays. Identified barriers included physical, psychological, and organizational aspects. Motivational aspects were based on improvements in physical fitness and mental well-being. Parents' behavior related to physical activities of their children differed between being supportive, inhibiting, and inert. Few patients received information about exercise during treatment by their physicians. CONCLUSIONS: Interventions that aim at maintaining physical activities during treatment and eliminating exercise barriers are required due to the patients' positive attitudes and multiple motivations toward exercise. These interventions need to be supervised and should include health-counseling programs for patients, parents, and physicians to underline the importance of physical activities in childhood cancer patients.

Evaluation of effects of busulfan and DMA on SOS in pediatric stem cell recipients.

BACKGROUND: Busulfan (Bu) is a DNA-alkylating agent used for myeloablative conditioning in stem cell transplantation in children and adults. While the use of intravenous rather than oral administration of Bu has reduced inter-individual variability in plasma levels, toxicity still occurs frequently after hematopoietic stem cell transplantation (HSCT). Toxicity (especially hepatotoxic effects) of intravenous (IV) Bu may be related to both Bu and/or N,N-dimethylacetamide (DMA), the solvent of Bu. In this study, we assessed the relation between the exposure of Bu and DMA with regards to the clinical outcome in children from two cohorts. METHODS: In a two-centre study Bu and DMA AUC (area under the curve) were correlated in pediatric stem cell recipients to the risk of developing SOS and to the clinical outcome. RESULT: In patients receiving Bu four times per day Bu levels >1,500 µmol/L minute correlate to an increased risk of developing a SOS. In the collective cohort, summarizing data of all 53 patients of this study, neither high area under the curve (AUC) of Bu nor high AUC of DMA appears to be an independent risk factor for the development of SOS in children. CONCLUSION: In this study neither Bu nor DMA was observed as an independent risk factor for the development of SOS. To identify subgroups (e.g., infants), in which Bu or DMA might be risk factors for the induction of SOS, larger cohorts have to be evaluated.

Population pharmacokinetics of intravenous busulfan in children: revised body weight-dependent NONMEM® model to optimize dosing.

PURPOSE: We developed a new population pharmacokinetic (PopPK) model for intravenous (i.v.) busulfan in children to evaluate the optimal method to personalize its dosing without concentration-time data. METHODS: PopPK analyses were done with NONMEM® 7.2. First, a model from Trame et al. was evaluated using an external dataset consisting of 24 children. Second, a revised model was built in a separate dataset of 82 children. Model evaluation was performed by using a standardized visual predictive check (SVPC) procedure and a bootstrap analysis (internal evaluation) and by comparison to an external dataset (external validation). RESULTS: The final model included body surface area (BSA) as an exponential function on volume of distribution (V) and actual body weight (ABW) as an allometric function on clearance (CL). The dosing nomogram for every 6 h administration derived from the final model is: dose[mg]=target AUC[mg×h/L]×3.04L/h×(ABW/16.1)0.797. Compared to other dosing strategies, differences were observed for the very small and obese patients. CONCLUSIONS: We revised our prior dosing nomogram after validation in a separate cohort of children. This dosing nomogram can be used to personalize i.v. busulfan doses without concentration-time data, but an additional prospective evaluation in the very small and obese children is needed.

Sports in pediatric oncology: the role(s) of physical activity for children with cancer.

Malignant disease and anticancer therapy dramatically affect daily life activities and participation in grassroots and high-performance sports. Specifically in childhood and adolescence such activities are relevant factors of individual development and social life. This review focuses on the inherent reduction of normal physical activity in pediatric oncology because this cutback additionally contributes to the level of burden of malignancies. Maintaining normality requires detailed analyses of disease-related and therapy-related restrictions and their justification. Relevant efforts should be stepped up to maintain physical activity levels during pediatric cancer therapy. Another aspect addresses direct therapeutic implications. Feasibility studies, nonrandomized as well as randomized investigations addressed therapeutic effects in acute hospital care, in bone marrow transplant settings, and in outpatient therapy. The overall summary shows positive effects on clinical and psychosocial outcome. Even if the basis of the data for children is still limited, there will be no doubt about a general impact of physical activity on acute side effects as well as late effects. In the areas of tension between context-related restrictions, the right to maintain normality wherever possible and the positive therapeutic and psychosocial perspectives of sports, strong efforts are needed to support physical activity wherever indicated, clarify contraindications, and overcome structural limitations.

Predictive performance of a physiologically based pharmacokinetic model of busulfan in children.

A physiologically based pharmacokinetic (PBPK) model of the DNA-alkylating agent busulfan was slightly modified and scaled from adults to children in order to predict the systemic busulfan drug exposure in children. Capitalizing on the recent major software release of PK-Sim®, we refined our PBPK model by implementing glutathione S transferase (GST) in 11 organs using the software integrated enzyme expression database. In addition, two irreversible binding processes (i.e., DNA and plasma protein binding) were applied by using Koff and KD values. The model was scaled from adults to children. Simulations were computed and compared to concentration-time data after intravenous (i.v.) busulfan administration to 36 children. Based on the results, an age-dependent enzyme activity and maturation ratio was tailored and evaluated with an external dataset consisting of 23 children. Initial adult to children scaling indicated lower clearance values for children in comparison to adults. Subsequent age-dependent maturation ratio resulted in three different age groups: Activity of busulfan-glutathione conjugate formation was 80%, 61%, and 89% in comparison to adults for children with an age of up to 2 years, > 2-6 years, and > 6-18 years, respectively. Patients of the evaluation dataset were simulated with a mean percentage error (MPE) for all patients of 3.9% with 3/23 children demonstrating a MPE of > ±30%. The PBPK model parameterization sufficiently described the observed concentration-time data of the validation dataset while showing an adequate predictive performance. This PBPK model could be helpful to determine the first dose of busulfan in children.

Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study.

PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

Population pharmacokinetics of escalating doses of caspofungin in a phase II study of patients with invasive aspergillosis.

Caspofungin (CAS) is approved for second-line management of proven or probable invasive aspergillosis at a dose of 50 mg once daily (QD). Preclinical and limited clinical data support the concept of the dose-dependent antifungal efficacy of CAS with preservation of its favorable safety profile. Little is known, however, about the pharmacokinetics (PKs) of higher doses of CAS in patients. In a formal multicenter phase II dose-escalation study, CAS was administered as a 2-h infusion at doses ranging from 70 to 200 mg QD. CAS PK sampling (n = 468 samples) was performed on day 1 and at peak and trough time points on days 4, 7, 14, and 28 (70 mg, n = 9 patients; 100 mg, n = 8 patients; 150 mg, n = 9 patients; 200 mg, n = 20 patients; total, n = 46 patients). Drug concentrations in plasma were measured by liquid chromatography tandem mass spectroscopy. Population pharmacokinetic analysis (PopPK) was performed using NONMEM (version 7) software. Model evaluation was performed using bootstrap analysis, prediction-corrected visual predictive check (pcVPC), as well as standardized visual predictive check (SVPC). The four investigated dose levels showed no difference in log-transformed dose-normalized trough levels of CAS (analysis of variance). CAS concentration data fitted best to a two-compartment model with a proportional-error model, interindividual variability (IIV) fitted best on clearance (CL), central and peripheral volume of distribution (V(1) and V(2), respectively) covariance fitted best on CL and V(1), interoccasion variability (IOV) fitted best on CL, and body weight fitted best as a covariate on CL and V(1) (CL, 0.411 liters/h ± 29% IIV; IOV on CL, 16%; V(1), 5.785 liters ± 29% IIV; intercompartmental clearance, 0.843 liters/h; V2, 6.53 liters ± 67% IIV). None of the other examined covariates (dose level, gender, age, serum bilirubin concentration, creatinine clearance) improved the model further. Bootstrap results showed the robustness of the final PopPK model. pcVPC and SVPC showed the predictability of the model and further confirmed the linear PKs of CAS over the dosage range of 70 to 200 mg QD. On the basis of the final model, geometric mean simulated peak plasma levels at steady state ranged from 13.8 to 39.4 mg/liter (geometric coefficient of variation, 31%), geometric mean trough levels ranged from 4.2 to 12.0 mg/liter (49%), and geometric mean areas under the concentration-time curves ranged from 170 to 487 mg · h/liter (34%) for the dosage range of 70 to 200 mg QD. CAS showed linear PKs across the investigated dosage range of 70 to 200 mg QD. Drug exposure in the present study population was comparable to that in other populations. (This study has been registered with the European Union Drug Regulating Authorities Clinical Trials website under registration no. 2006-001936-30 and at ClinicalTrials.gov under registration no. NCT00404092.).

Anti-Escherichia coli asparaginase antibody levels determine the activity of second-line treatment with pegylated E coli asparaginase: a retrospective analysis within the ALL-BFM trials.

Hypersensitivity reactions limit the use of the antileukemic enzyme asparaginase (ASE). We evaluated Ab levels against Escherichia coli ASE and ASE activity in 1221 serum samples from 329 patients with acute lymphoblastic leukemia who had received ASE treatment according to the ALL-BFM 2000 or the ALL-REZ BFM 2002 protocol for primary or relapsed disease. ASE activity during first-line treatment with native E coli ASE and second-line treatment with pegylated E coli ASE was inversely related to anti-E coli ASE Ab levels (P < .0001; Spearman rank order correlation). An effect on ASE activity during second-line treatment with pegylated E coli ASE was, however, only observed when anti-E coli ASE Ab levels were high (> 200 AU/mL). In the presence of moderate or intermediate Ab levels (6.25-200 AU/mL) the switch from native to pegylated E coli ASE resulted in a significant increase of ASE activity above the threshold of 100 U/L (P < .05). Erwinia chrysanthemi ASE activity was not correlated with anti-E coli ASE Ab levels. Erwinia ASE was found to be the best ASE alternative if Ab levels against E coli ASE exceed 200 AU/mL. This retrospective analysis is the first to describe the relationship between the level of anti-E coli ASE Abs and serum activity of pegylated E coli ASE used second-line after native E coli ASE.

No evidence of increased asparagine levels in the bone marrow of patients with acute lymphoblastic leukemia during asparaginase therapy.

BACKGROUND: Mesenchymal cells (MSCs) in bone marrow (BM) may produce asparagine and form protective niches for leukemic cells. In vitro, this led to high levels of asparagine and conferred asparaginase resistance to acute lymphoblastic leukemia (ALL) cells. The aim of this study was to investigate whether MSCs or other cells in BM indeed produce such significant amounts of asparagine in vivo as to result in clinical asparaginase resistance. PROCEDURE: Twenty-six patients with newly diagnosed ALL were enrolled. All children received induction chemotherapy according to the Dutch Childhood Oncology Group (DCOG) ALL-10 protocol. Asparaginase was administered from days 12-33. Asparaginase, asparagine, aspartic acid, glutamine, and glutamic acid levels were measured in BM and blood at diagnosis, days 15, 33, and 79. RESULTS: Median asparaginase trough levels were not significantly different at days 15 and 33. Only at diagnosis, asparagine level was significantly higher in BM than in blood (P = 0.001). Asparagine levels were all below the lower limit of quantification in BM and blood at days 15 and 33. However, aspartic acid level in BM was significantly higher than in blood (P < 0.001) at diagnosis, and also at days 15, 33, and 79. CONCLUSIONS: We demonstrate higher aspartic acid levels in BM compared to blood; however, no increased asparagine levels were seen during induction therapy containing asparaginase in BM when compared to blood. Therefore, increased asparagine synthesis by MSCs is of relevance for resistance to asparaginase of leukemic cells in vitro, but it is questionable whether this leads to asparaginase resistance in childhood ALL patients.