Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia: a national, prospective, longitudinal study in the Netherlands.

OBJECTIVES: Health-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse, which is now reflected by the stratification of patients into three risk groups who receive treatment of differing intensities. This study is the first to evaluate the longitudinal course of HRQoL in light of these adjustments and identify determinants of HRQoL. DESIGN: Two prospective, national cohort studies (add-on studies within the two most recent treatment protocols for children with ALL (ALL-10 and ALL-11)). SETTING: Dutch paediatric oncology hospitals between October 2006 and October 2009 (ALL-10) and between August 2013 and July 2017 (ALL-11). PARTICIPANTS: Patients with ALL (2-18 years) are treated according to the ALL-10 or ALL-11 treatment protocol. Patients treated according to the ALL-10 protocol only completed a cancer-specific QoL measure and patients treated according to the ALL-11 protocol completed both a cancer-specific and generic QoL measure (see below). OUTCOME MEASURES: HRQoL, assessed with parent-proxy questionnaires (PedsQL Generic and Cancer module) within the first 5 months (T0), at 1 year (T1), 2 years (T2) and 3 years (T3) after diagnosis. The proportion of patients with clinically relevant generic HRQoL impairment was compared with healthy norm values. Multivariable mixed model analyses were used to evaluate the development of HRQoL over time and its medical and sociodemographic determinants (collected on enrolment). RESULTS: Of the ALL-10 cohort, 132 families participated and of the ALL-11 cohort, 136 families participated (268 total). Thus, cancer-specific HRQoL assessments were available for 268 patients (median age 5.3 years (IQR 6.15), 56.0% boys, 69.0% medium-risk ALL), and generic HRQoL assessments for 136 patients (median age 4.8 years (IQR 6.13), 60.3% boys, 75.0% medium-risk ALL). Generic HRQoL improved between timepoints T0 and T3 (total score B 16.1, 95% CI 12.2 to 20.1, p<0.001), but did not restore to normal 1 year after the end of treatment: 28.0% of children remained impaired compared with 16% in the general population (p=0.003). Cancer-specific HRQoL generally improved from T0 to T2 (Pain B 11.3, 95% CI 7.1 to 15.5; Nausea B 11.7, 8.4 to 15.1; Procedural Anxiety B 19.1, 14.8 to 23.4; Treatment Anxiety B 12.8, 9.5 to 16.0; Worry B 3.5, 0.6 to 6.3; Communication B 8.5, 5.0 to 11.9; all p<0.001 except for Worry (p=0.02)), while Physical Appearance and Cognitive Functioning remained stable. Higher treatment intensity and experiencing pain or simultaneous chronic illness were associated with lower HRQoL over time for multiple subscales. CONCLUSIONS: HRQoL impairment is prevalent during and after ALL treatment. Patients with standard-risk ALL and reduced treatment intensity have better HRQoL than patients in higher risk groups. Systematic monitoring of HRQoL is of utmost importance in order to provide timely psychosocial interventions and supportive care.

Azacitidine (Vidaza®) in Pediatric Patients with Relapsed Advanced MDS and JMML: Results of a Phase I/II Study by the ITCC Consortium and the EWOG-MDS Group (Study ITCC-015).

BACKGROUND: Advanced myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematological malignancies in children. A second allograft is recommended if a relapse occurs after hematopoietic stem cell transplantation, but the outcome is poor. OBJECTIVE: We conducted a phase I/II multicenter study to evaluate the safety, pharmacokinetics, and activity of azacitidine in children with relapsed MDS/JMML prior to the second hematopoietic stem cell transplantation. METHODS: Patients enrolled from June 2013 to March 2019 received azacitidine intravenously/subcutaneously once daily on days 1-7 of a 28-day cycle. The MDS and JMML cohorts followed a two-stage design separately, with a safety run-in for JMML. Response and safety data were used to evaluate efficacy and establish the recommended dose. Pharmacokinetics was also analyzed. The study closed prematurely because of low recruitment. RESULTS: Six patients with MDS and four patients with JMML received a median of three and five cycles, respectively. Azacitidine 75 mg/m2 was well tolerated and plasma concentration-time profiles were similar to observed in adults. The most prevalent grade 3-4 adverse event was myelotoxicity. No responses were seen in patients with MDS, but 83% achieved stable disease; four patients underwent an allotransplant. Overall response rate in the JMML cohort was 75% (two complete responses; one partial response) and all responders underwent hematopoietic stem cell transplantation. One-year overall survival was 67% (95% confidence interval 38-100) in MDS and 50% (95% confidence interval 19-100) in JMML. CONCLUSIONS: Azacitidine 75 mg/m2 prior to a second hematopoietic stem cell transplantation is safe in children with relapsed MDS/JMML. Although the long-term advantage remains to be assessed, this study suggests that azacitidine is an efficacious option for relapsed JMML. CLINICAL TRIAL REGISTRATION: EudraCT 2010-022235-10.

Case series on clinical applications of liquid biopsy in pediatric solid tumors: towards improved diagnostics and disease monitoring.

Background and aims: Solid tumors account for about 30% of all pediatric cancers. The diagnosis is typically based on histological and molecular analysis of a primary tumor biopsy. Liquid biopsies carry several advantages over conventional tissue biopsy. However, their use for genomic analysis and response monitoring of pediatric solid tumors is still in experimental stages and mostly performed retrospectively without direct impact on patient management. In this case series we discuss six clinical cases of children with a solid tumor for whom a liquid biopsy assay was performed and demonstrate the potential of liquid biopsy for future clinical decision making. Methods: We performed quantitative real-time PCR (RT-qPCR), droplet digital PCR (ddPCR) or reduced representation bisulphite sequencing of cell-free DNA (cfRRBS) on liquid biopsies collected from six pediatric patients with a solid tumor treated between 2017 and 2023 at the Princess Máxima Center for Pediatric Oncology in the Netherlands. Results were used to aid in clinical decision making by contribution to establish a diagnosis, by prognostication and response to therapy monitoring. Results: In three patients cfRRBS helped to establish the diagnosis of a rhabdomyosarcoma, an Ewing sarcoma and a neuroblastoma (case 1-3). In two patients, liquid biopsies were used for prognostication, by MYCN ddPCR in a patient with neuroblastoma and by RT-qPCR testing rhabdomyosarcoma-specific mRNA in bone marrow of a patient with a rhabdomyosarcoma (case 4 and 5). In case 6, mRNA testing demonstrated disease progression and assisted clinical decision making. Conclusion: This case series illustrates the value of liquid biopsy. We further demonstrate and recommend the use of liquid biopsies to be used in conjunction with conventional methods for the determination of metastatic status, prognostication and monitoring of treatment response in patients with pediatric solid tumors.

Fatigue trajectories during pediatric ALL therapy are associated with fatigue after treatment: a national longitudinal cohort study.

OBJECTIVE: Fatigue is one of the most prevalent and distressing symptoms reported by survivors of childhood cancer. There is currently a lack of longitudinal studies on cancer-related fatigue, and especially on the relationship between the course of fatigue during treatment and fatigue at follow-up. The purpose of the current study was therefore to investigate if the course of fatigue during treatment, treatment intensity, serious adverse events, sex, or age at diagnosis are associated with cancer-related fatigue after treatment. METHODS: Participants were 92 children and adolescents diagnosed with acute lymphoblastic leukemia (mean age at diagnosis was 6.26 years). Fatigue was measured with PedsQL multidimensional fatigue scale proxy reports 5 months after diagnosis, 12 months after diagnosis, 24 months after diagnosis, and at follow-up 12 months after end of treatment. The effect of patient and treatment characteristics on fatigue reported at follow-up was tested through logistic regression analyses. RESULTS: The course of fatigue during treatment significantly predicted fatigue reported at follow-up for general fatigue (p = .038, OR = 9.20), sleep/rest fatigue (p = .011, OR = 15.48), and cognitive fatigue (p < .001, OR = 10.78). None of the other variables were associated with fatigue at follow-up for any of the subscales. CONCLUSIONS: The findings demonstrate that fatigue reported during treatment can predict fatigue at follow-up. These results stress the need for longitudinal assessments. Healthcare professionals need to be aware that pediatric patients who are fatigued during treatment need to receive additional attention and timely interventions since cancer-related fatigue will not resolve by itself in the first year after end of treatment.

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'.

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival.

Anti-GD2 Based Immunotherapy Prevents Late Events in High-Risk Neuroblastoma Patients over 18 Months at Diagnosis.

BACKGROUND: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the long-term efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. METHODS: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with single-agent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy. RESULTS: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64 ± 7% and 49 ± 8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57 ± 7% and 41 ± 8%, respectively (p = 0.16). In the subgroup of patients ≥ 18 months, 5-yr OS was 63 ± 8% and 39 ± 9, respectively (p = 0.04) and EFS 54 ± 8% and 29 ± 8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events. CONCLUSIONS: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis.

Recurrence of a Mediastinal Germ-Cell Tumor as a Somatic-Type Malignancy: A Complex Case Report.

Background and case: An adolescent male presented with a second mediastinal tumor 1.5 years after treatment of a proven malignant germ-cell tumor in that location. The differential diagnosis included a recurrent germ-cell tumor or a non-germ cell malignancy. Serum tumor markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) were negative. The first biopsy was not informative, and the second biopsy gave a broad differential diagnosis including secondary non-germ cell malignancy using histology and immunohistochemistry. DNA methylation profiling, RNA sequencing, and targeted microRNA371a-3p profiling was subsequently performed, without a supportive result. After resection of the tumor the definitive diagnosis yielded two secondary non-germ cell malignancies in the form of a leiomyosarcoma and a solitary neuro endocrine carcinoma (NEC). In spite of the differences between the molecular profiles of the initial germ-cell tumor, the leiomyosarcoma and large-cell NEC are clonally related, as determined by the presence of identical chromosomal breakpoints. The copy number profiles suggest an initial polyploidization step, followed by various independent chromosomal gains and losses. This case demonstrates that germ-cell tumors must be evaluated carefully, including molecularly, in which the non-germ cell malignancy is negative for miR-371a-3p, both in tissue as well as in serum, in contrast to the primary tumor. We conclude that the patient presented with a primary type II mediastinal GCT and, a year and a half later, followed by a leiomyosarcoma and a large-cell NEC presenting as two secondary somatic-type malignancies clonally related to the original GCT. Conclusions: Malignant germ-cell tumors are known to recur as a somatic-type malignancy in very rare cases. This case report illustrates the challenges faced in defining the nature and clonality of the secondary somatic-type malignancies.

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study.

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.

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.

Cisplatin and carboplatin pharmacokinetics in a pediatric patient with hepatoblastoma receiving peritoneal dialysis.

PURPOSE: Cisplatin and carboplatin are frequently used drugs in the treatment of pediatric hepatoblastoma. Dosing guidelines for these drugs in children requiring peritoneal dialysis are lacking. Here, we describe the case of a 3-year-old boy with pre-existing end-stage renal disease on peritoneal dialysis, requiring treatment with cisplatin and carboplatin for hepatoblastoma. METHODS: Pharmacokinetic data were generated to support clinical dosing decisions, with the aim of adequate exposure and minimal toxicity. In the first chemotherapy cycle, 25% of the standard cisplatin dose and 75% of the carboplatin dose, calculated using the pediatric Calvert formula, were administered. Free platinum concentrations were determined in plasma ultrafiltrate and dialysate samples drawn after administration of cis- and carboplatin. RESULTS: Cisplatin was well tolerated and the observed AUC of cisplatin were 15.3 and 14.3 mg/L h in cycles 1 and 3, respectively. The calculated AUC of carboplatin in cycle 1 (9.8 mg/mL min) exceeded target AUC of 6.5 mg/mL min and toxicity was observed; therefore, the dose was reduced in cycles 2 and 3. The observed AUC in cycles 2 and 3 was 5.4 and 5.7 mg/mL min respectively. Platinum concentrations in the dialysate showed that 3-4% of the total dose of cisplatin and 10-12% of the total dose of carboplatin were excreted via peritoneal dialysis. Chemotherapy enabled extended hemihepatectomy and complete remission was achieved. CONCLUSION: This report shows that it is feasible to measure AUCs for both drugs and to individualize the dose of these drugs according to the PK results and clinical parameters. Our advice for future cases would be to calculate the starting dose of carboplatin using the (pediatric) Calvert formula, assuming a dialytic clearance of zero, and to adjust the dose if required, based on therapeutic drug monitoring.

Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology.

In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure-response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin ) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure-efficacy relationship from adults to children and propose target Cmin values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.

High prevalence of parent-reported sleep problems in pediatric patients with acute lymphoblastic leukemia after induction therapy.

OBJECTIVE: To assess sleep problems (prevalence and predictors) in pediatric patients with acute lymphoblastic leukemia (ALL) after the most intensive phase of therapy (induction). METHODS: Patients (≥2 years) treated according to the Dutch ALL-11 protocol were included. Sleep was measured using parent-reports and self-reports (Children's Sleep Habits Questionnaire; CSHQ) and actigraphy. Parental sleep (Medical Outcome Study Sleep Scale) and distress and parenting problems (Distress Thermometer for Parents) were assessed with questionnaires. Z-scores were calculated for total CSHQ scores using age-appropriate scores of healthy Dutch children. The prevalence of sleep problems (defined as a Z-score > 1) in patients with ALL was compared to healthy children (chi-square tests). Actigraphic sleep estimates were collected in healthy Dutch children (n = 86, 2-18 years) for comparison with patients (linear regression). Determinants of parent-reported child sleep (total CSHQ Z-score) were identified with regression models. RESULTS: Responses were collected for 124 patients (response rate 67%), comprising 123 parent-reports, 34 self-reports, and 69 actigraphy assessments. Parents reported sleep problems in 38.0% of the patients compared to 15.2% in healthy children (P < .001). Patients reported fewer sleep problems themselves: 12.1% compared to 15.8% in healthy children (P = .33). Total time in bed (B (95% CI): 22.89 (9.55-36.22)) and total sleep time (B (95% CI):16.30 (1.40-31.19)), as derived from actigraphy, were significantly longer in patients. More parent-reported child sleep problems were predicted by parenting problems, more parental sleep problems, bedroom sharing, and child's sleep medication use (explained variance: 27.4%). CONCLUSIONS: Systematic monitoring of child and parental sleep and implementation of effective interventions may be a gateway to improve quality of survival in pediatric ALL.

Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia.

STUDY OBJECTIVES: To compare sleep-wake rhythms, melatonin, and cancer-related fatigue in pediatric patients with acute lymphoblastic leukemia (ALL) to healthy children and to assess the association between sleep-wake outcomes and cancer-related fatigue. METHODS: A national cohort of ALL patients (2-18 years) was included. Sleep-wake rhythms were measured using actigraphy and generated the following variables: Interdaily stability (IS): higher IS reflects higher stability; intradaily variability (IV): lower IV indicates less fragmentation; L5 and M10 counts: activity counts during the five least and 10 most active hours, respectively; and relative amplitude (RA): the ratio of L5 and M10 counts (higher RA reflects a more robust rhythm). The melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), was assessed in urine. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Using regression models sleep-wake rhythms, aMT6s, and cancer-related fatigue were compared to healthy children and associations between sleep-wake outcomes and cancer-related fatigue were assessed in ALL patients. RESULTS: In total, 126 patients participated (response rate: 67%). IS, RA, and M10 counts were lower in patients compared to healthy children (p < 0.001). aMT6s levels were comparable to healthy children (p = 0.425). Patients with ALL were more fatigued compared to healthy children (p < 0.001). Lower IS, RA and M10 counts and higher IV were significantly associated with more parent-reported cancer-related fatigue. Associations between sleep-wake rhythms and self-reported cancer-related fatigue were not statistically significant. CONCLUSIONS: Sleep-wake rhythm impairment is associated with more cancer-related fatigue in pediatric ALL patients. Interventions aimed to improve sleep hygiene and encourage physical activity may reduce cancer-related fatigue.

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

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 HD-MTX 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.

Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study.

Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m2/day × 5 days) and liposomal daunorubicin (40-80 mg/m2/day) were administered with cytarabine (2 g/m2/day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2clofarabine; 60 mg/m2liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.

Design of a drug-drug interaction study of vincristine with azole antifungals in pediatric cancer patients using clinical trial simulation.

BACKGROUND: The aim of the current work was to perform a clinical trial simulation (CTS) analysis to optimize a drug-drug interaction (DDI) study of vincristine in children who also received azole antifungals, taking into account challenges of conducting clinical trials in this population, and, to provide a motivating example of the application of CTS in the design of pediatric oncology clinical trials. PROCEDURE: A pharmacokinetic (PK) model for vincristine in children was used to simulate concentration-time profiles. A continuous model for body surface area versus age was defined based on pediatric growth curves. Informative sampling time windows were derived using D-optimal design. The CTS framework was used to different magnitudes of clearance inhibition (10%, 25%, or 40%), sample size (30-500), the impact of missing samples or sampling occasions, and the age distribution, on the power to detect a significant inhibition effect, and in addition, the relative estimation error (REE) of the interaction effect. RESULTS: A minimum group specific sample size of 38 patients with a total sample size of 150 patients was required to detect a clearance inhibition effect of 40% with 80% power, while in the case of a lower effect of clearance inhibition, a substantially larger sample size was required. However, for the majority of re-estimated drug effects, the inhibition effect could be estimated precisely (REE < 25%) in even smaller sample sizes and with lower effect sizes. CONCLUSION: This work demonstrated the utility of CTS for the evaluation of PK clinical trial designs in the pediatric oncology population.

Clinical evaluation of vancomycin dosage in pediatric oncology patients.

Vancomycin trough serum concentrations were below therapeutic range (8-15 mg/L) in 58% of 124 pediatric oncology patients receiving 60 mg/kg/d divided qid. Patients <6 and between 6 and 12 years had significantly lower trough concentrations than patients >12 years. A vancomycin dosage of 60 mg/kg/d is inadequate for pediatric oncology patients >12 years.

Severe skin toxicity in pediatric oncology patients treated with voriconazole and concomitant methotrexate.

We report the occurrence of skin toxicities in pediatric oncology patients on concomitant treatment with voriconazole and methotrexate (MTX). Of 23 patients who received this combination, 11 patients suffered from cheilitis and/or photosensitivity. In contrast, only in 1 of 9 patients who received voriconazole without MTX was photosensitivity observed. A mechanism of action was not able to be identified. We describe two cases with severe skin toxicities. Caution is warranted when using voriconazole and concomitant MTX.

Optimizing drug development of anti-cancer drugs in children using modelling and simulation.

Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population.