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PURPOSEThe 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 METHODSA 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.RESULTSBy 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).CONCLUSIONAdditional 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.

The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR.

Background and Objectives: Besides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics. Methods: PEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m2, intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed. Results: High pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgGprior and IgMprior were significant covariates; the stronger effect was observed for anti-PEG IgMprior. Hockey stick models best described the data. For anti-PEG IgMprior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgMprior alone. Antibody levels post administration were not associated with an effect on clearance. Conclusion: Pre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.)

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.

Background and Objectives: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. Methods: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. Results: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. Conclusion: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0−∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. (www.clinicaltrials.gov, NCT01117441, first submitted date: May 3, 2010).

Background: Despite its cardiotoxicity doxorubicin is widely used for the treatment of paediatric malignancies. Current treatment regimens appear to be suboptimal as treatment strategies vary and do not follow a clear pharmacological rationale. Standardisation of dosing strategies in particular for infants and younger children is required but is hampered by scarcely defined exposure-response relationships. The aim is to provide a rational dosing concept allowing for a reduction of variability in systemic therapy intensity and subsequently unforeseen side effects. Methods: Doxorubicin plasma concentrations in paediatric cancer patients were simulated for different treatment schedules using a population pharmacokinetic model which considers age-dependent differences in doxorubicin clearance. Overall drug exposure and peak concentrations were assessed. Simulation results were used to support a three round Delphi consensus procedure with the aim to clarify the pharmacological goals of doxorubicin dosing in young children. A group of 28 experts representing paediatric trial groups and clinical centres were invited to participate in this process. Results: Pharmacokinetic simulations illustrated the substantial differences in therapy intensity associated with current dosing strategies. Consensus among the panel members was obtained on a standardised a priori dose adaptation that individualises doxorubicin doses based on age and body surface area targeting uniform drug exposure across children treated with the same protocol. Further, a reduction of peak concentrations in very young children by prolonged infusion was recommended. Conclusions: An approach to standardise current dose modification schemes in young children is proposed. The consented concept takes individual pharmacokinetic characteristics into account and involves adaptation of both the dose and the infusion duration potentially improving the safety of doxorubicin administration.

Objective: Cranial Radiotherapy (CRT) is a common aspect of treatment for brain tumours in childhood. Larger cochlear dose of radiation correlates with greater hearing loss (eg. Hua et al., 2008), especially in combination with Cisplatin chemotherapy (eg. Paulinho et al, 2010). Animal studies and clinical studies in adults suggest asymmetrical hearing loss (Miller et al., 2007; Van der Putten, 2006).Materials and Methods: We initiated a retrospective study in a pediatric population with brain tumours to investigate the effects of CRT on audiological thresholds, as part of our involvement in PANCare-Life. Initial results include a comparison of post-chemotherapy thresholds of 186 patients (57 who had CRT, 129 who did not) to investigate progressive audiological changes after cessation of platin treatment. Thresholds were categorized according to the Münster system, focusing on minimal high-frequency changes (Schmidt et al., 2007).Results: The CRT and non-CRT groups were characterized by asymmetrical vs symmetrical post-treatment hearing losses respectively. A robust tendency (p= 0.05, Fisher's exact) towards asymmetrical deterioration was found in the CRT group. No significant differences were found in the estimated mean cochlear dose of CRT per ear (means of 42.5 and 47 Gy (t=0.18) for the least and most irradiated ears respectively) given to a group of 19 CRT patients. Inter-ear hearing thresholds for this group also showed no significant difference which, although it does not directly support the idea of asymmetrical cranial radiation as a cause of increased asymmetrical hearing loss (Van den Putten, 2006), does take a complimentary position.Conclusion: These findings underline the necessity of audiological follow up after cessation of platin therapy, especially in children with combined cranial irradiation.

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m2 every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m2 2-3 times week

Cisplatin ist ein hochwirksames Chemotherapeutikum für die Behandlung unterschiedlicher Tumoren im Kindesalter. Als Nebenwirkung kann ein Hörverlust, beginnend im Hochtonbereich auftreten. Als Risikofaktoren für das Auftreten eines Hörverlustes wurden unter anderem ein geringes Alter der Patienten, die kumulative Cisplatin-Gesamtdosis, das Infusionsschema und genetische Faktoren beschrieben. Die pädaudiologischen und onkologischen Daten von 21 Patienten, die zwischen 2002 und 2008 mit einer Cisplatin-haltigen Chemotherapie begannen, vor Therapie ein normales seitengetrenntes Tonschwellenaudiogramm zeigten und unter der Therapie eine Hörstörung entwickelten, wurden ausgewertet. Eine ototoxische Wirkung des Cisplatins wurde angenommen, wenn eine Hörverschlechterung auf mindestens Grad 2a (Münsteraner Klassifikation) auf einem Ohr vorlag. Die kumulative relative (pro m2 Körperoberfläche) Gesamtdosis bis zum erstmaligen Auftreten einer Hörstörung variierte von 70 bis 480 mg/m2, der Mittelwert betrug 219,05 mg/m2 (SD 135,24). Es zeigt sich somit eine große individuelle Toleranz gegenüber einer Cisplatin-induzierten Ototoxizität. Dies lässt darauf schließen, dass neben der Dosis vor allem andere, individuelle (genetische) Faktoren für die Toleranz gegenüber Cisplatin verantwortlich sind.

Cisplatin wird in der pädiatrischen Onkologie mit Erfolg bei der Behandlung verschiedener Tumoren eingesetzt. Die hohe therapeutische Effektivität wird jedoch durch die Oto- und Nephrotoxizität limitiert. Histologische Untersuchungen zeigen nach Cisplatin-Gabe eine vermehrte Akkumulation von Cisplatin-DNA-Addukten in den proximalen Tubuluszellen der Niere und den Marginalzellen der Stria vascularis des Innenohrs. In beiden Geweben wird der LDL-Rezeptor Megalin hoch exprimiert. Megalin ist verantwortlich für die Endozytose verschiedener Moleküle, unter anderem auch der ebenfalls oto- und nephrotoxischen Aminoglykoside. Ein Zusammenhang zwischen der Aminoglykosid-Toxizität und Megalin konnte bereits hergestellt werden. Unter der Hypothese, dass Megalin an der Cisplatin-induzierten Ototoxizität beteiligt ist, untersuchten wir die Häufigkeit der Single-Nucleotide-Polymorphismen (SNP) rs2075252 und rs4668123 bei je 25 Patienten mit und ohne Entwicklung einer Hörstörung nach Cisplatin-Therapie. Eingeschlossen wurden nur Patienten ohne zusätzliche ototoxische Medikation, kranielle Bestrahlung oder vorbestehenden Hörschaden. Das A-Allel des SNPs rs2075252 trat signifikant häufiger in der Gruppe mit als in der ohne Hörstörung auf (0.32 vs. 0.14) (chi2=5.83, p<0.02; OR 3.45; 95%CI 1.11-11.2). Diese Untersuchung läßt erstmals eine Beteiligung des Megalins an der Pathogenese der Cisplatin-Ototoxizität vermuten.

Zu den dosislimitierenden Nebenwirkungen des Cisplatins zählen seine Oto- und Nephrotoxizität. Ein wesentlicher Pathomechanismus besteht in der Schädigung der cochleären Haarzellen. Ein frühes Zeichen niedriger Cisplatin-Toleranz bzw. einer Haarzellschädigung kann daher in einer Änderung der otoakustischen Emissionen vermutet werden.Wir untersuchten 15 Kinder und Jugendliche mit Osteosarkom, welche gemäß COSS96-Schema (40 mg/m² als 72h-Dauerinfusion) behandelt wurden vor und während der Chemotherapie. Neben pädaudiologischen Kontrollen im Intervall erfolgte unter der Cisplatininfusion die Messung der TEOAE 24, 72 und 96h nach Infusionsbeginn. Gleichzeitig erfolgten laborchemische Bestimmungen des Cisplatins, der Elektrolyte und des Kreatinins. Von 15 Patienten entwickelten 9 eine Hörstörung mit einem Hörverlust von mehr als 20 dB ab 4 kHz, davon 3 auch unter 4 kHz. Im Gruppenvergleich lieferten die TEOAE unter Infusion keinen sicheren Vorhersagewert zur Ausbildung einer Hörstörung. Die Cisplatindosen bis zum ersten Auftreten einer Hörstörung differierten deutlich (zwischen 165 und 516 mg). Signifikante Unterschiede zwischen den Gruppen mit und ohne Hörstörung zeigten sich beim anorganischen Phosphat, Magnesium und Kreatinin. Die Untersuchungen lassen vermuten, dass die Patienten, die eine Hörstörung entwickeln, auch Zeichen einer Beeinträchtigung der Nierenfunktion aufweisen.