BackgroundDexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and... Show moreBackgroundDexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors.MethodsPatients with ALL aged 3-18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or >= three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2.ResultsWe included 105 patients, 61% were boys. Median age was 5.3 years (range: 3-18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28-0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22-0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96-0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2-3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2.ConclusionPhysical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course.Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy. After a 5-day dexamethasone course. Physical frailty increased with 13.5% in pediatric ALL patients. A poorer physical state at start of a dexamethasone course (lower muscle mass, muscle strength, or slower movement ability) was prognostic for developing frailty after a dexamethasone course.image Show less
Pieters, R.; Groot-Kruseman, H. de; Fiocco, M.; Verwer, F.; Overveld, M. van; Sonneveld, E.; ... ; Boer, M. den 2023
Purpose The ALL10 protocol improved outcomes for children with ALL by stratifying and adapting therapy into three minimal residual disease-defined risk groups: standard risk, medium risk (MR), and... Show morePurpose The ALL10 protocol improved outcomes for children with ALL by stratifying and adapting therapy into three minimal residual disease-defined risk groups: standard risk, medium risk (MR), and high risk. IKZF1-deleted (IKZF1del) ALL in the largest MR group still showed poor outcome, in line with protocols worldwide, accounting for a high number of overall relapses. ALL10 showed high toxicity in Down syndrome (DS) and excellent outcome in ETV6::RUNX1 ALL. Poor prednisone responders (PPRs) were treated as high risk in ALL10. In ALL11, we prolonged therapy for IKZF1del from 2 to 3 years. We reduced therapy for DS by omitting anthracyclines completely, for ETV6::RUNX1 in intensification, and for PPR by treatment as MR.Methods Eight hundred nineteen patients with ALL (age, 1-18 years) were enrolled on ALL11 and stratified as in ALL10. Results were compared with those in ALL10.Results The five-year overall survival (OS), event-free survival (EFS), cumulative risk of relapse (CIR), and death in complete remission on ALL11 were 94.2% (SE, 0.9%), 89.0% (1.2), 8.2% (1.1), and 2.3% (0.6), respectively. Prolonged maintenance for IKZF1del MR improved 5-year CIR by 2.2-fold (10.8% v 23.4%; P = .035) and EFS (87.1% v 72.3%; P = .019). Landmark analysis at 2 years from diagnosis showed a 2.9-fold reduction of CIR (25.6%-8.8%; P = .008) and EFS improvement (74.4%-91.2%; P = .007). Reduced therapy did not abrogate 5-year outcome for ETV6::RUNX1 (EFS, 98.3%; OS, 99.4%), DS (EFS, 87.0%; OS, 87.0%), and PPR (EFS, 81.1%; OS, 94.9%).Conclusion Children with IKZF1del ALL seem to benefit from prolonged maintenance therapy. Chemotherapy was successfully reduced for patients with ETV6::RUNX1, DS, and PPR ALL. It has to be noted that these results were obtained in a nonrandomized study using a historical control group. Show less
Hulst, A.M. van; Akker, E.L.T. van den; Verwaaijen, E.J.; Fiocco, M.; Rensen, N.; Litsenburg, R.R.L. van; ... ; Heuvel-eibrink, M.M. van den 2023
Background: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who... Show moreBackground: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding.Methods: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect.Results: The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect-2.05 (95% confidence interval (CI)-6.00-1.90). Also, no benefit from hydrocortisone compared to pla-cebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL.Conclusions: Hydrocortisone, when compared to placebo, had no additional effect in redu-cing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hy-drocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. Trial registration: NetherlandsTrial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/).(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/). Show less
Steeg, A.F.W. van der; Jans, M.; Tytgat, G.; Fiocco, M.F.; Ven, C. van de; Scheltinga, C.E.J.T. van; ... ; Wijnen, M.H.W.A. 2023
Introduction. In the Netherlands pediatric oncological care for solid tumours is concentrated in one centre since November 2014. One of the most frequently diagnosed solid non-brain tumours in... Show moreIntroduction. In the Netherlands pediatric oncological care for solid tumours is concentrated in one centre since November 2014. One of the most frequently diagnosed solid non-brain tumours in children is the neuroblastoma. Results of surgical treatment of neuroblastoma since the start of this centralization are presented and compared to a historic cohort. Methods. The new national cohort of neuroblastoma (n = 111) consists of all consecutive patients treated be-tween January 1st, 2015 and April 1st, 2021. The historic neuroblastoma cohort consists of all operated neuroblastoma patients in the Netherlands between 1998 and 2014 (n = 244). Intra-operative compli-cations and surgical outcome were registered. Post-operative complications were divided in short (<30 days after surgery) and long term (>30 days). The severity of complications was graded using the Clavien Dindo Classification (CDC) system. Results. Intraoperative outcomes showed significant differences in favour of the new cohort with less blood loss (p < 0.001), fewer vascular complications (p < 0.001) and shorter duration of surgery (p < 0.001). Short term complications were comparable in numbers, but significantly more patients had CDC grade 3/ 4/5 complications in the historic cohort (p = 0.005). Long term complications did not differ. Estimated overall survival showed a better survival in the new cohort (log rank 0.022). Conclusion. Centralization of care for neuroblastoma patients has led to a significant improvement of both intraoperative outcomes and short term complications. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Verwaaijen, E.J.; Torre, P. van der; Vormoor, J.; Pieters, R.; Fiocco, M.; Hartman, A.; Heuvel-Eibrink, M.M. van den 2023
Simple Summary Children treated for hemato-oncological diseases are at risk of muscle deterioration, such as loss of muscle mass and muscle weakness, with consequent impaired physical functioning.... Show moreSimple Summary Children treated for hemato-oncological diseases are at risk of muscle deterioration, such as loss of muscle mass and muscle weakness, with consequent impaired physical functioning. An easy screening tool will facilitate the early identification of children at risk and will support clinical decision making. We investigated the accuracy of an easy screening tool: the pediatric SARC-F (PED-SARC-F), for identifying functional sarcopenia in pediatric hemato-oncology patients. Functional sarcopenia indicates low muscle strength combined with low physical performance. We showed that the PED-SARC-F has a 90% accuracy in identifying pediatric hemato-oncology patients with functional sarcopenia. A PED-SARC-F cut-off point of >= 5 had the highest specificity (91%) and limits unnecessary assessments in patients who are not at risk of sarcopenia. This tool can be used to identify children that need a physiotherapy assessment and further interventions to prevent physical deterioration during and shortly after treatment for a hemato-oncology disease. Sarcopenia in pediatric hemato-oncology patients is undesirable because of the consequences it may have for treatment continuation and outcome, physical abilities and participation in daily life. An easy-to-use screening tool for sarcopenia will facilitate the identification of children at risk who need interventions to prevent serious physical deterioration. In the elderly, the use of the SARC-F score as a case-finding tool for sarcopenia is recommended. The aim of this cross-sectional study was to investigate the accuracy of the pediatric SARC-F (PED-SARC-F) for identifying sarcopenia in pediatric hemato-oncology patients, including the determination of a cut-off point for clinical use. Patients 3-20 years of age, under active treatment or within 12 months after treatment cessation were eligible. Patients had a physiotherapy assessment including a PED-SARC-F (0-10) and measurements of muscle strength (handheld dynamometry), physical performance (various tests) and/or muscle mass (bio-impedance analysis), as part of the standard of care. Spearman's correlation coefficient (r(s)) between the PED-SARC-F and physiotherapy outcomes were calculated. Structural sarcopenia was defined as low appendicular skeletal muscle mass (ASMM) in combination with low muscle strength and/or low physical performance. Functional sarcopenia indicated low muscle strength combined with low physical performance. Multiple logistic regression models were estimated to study the associations between the PED-SARC-F and structural/functional sarcopenia. To evaluate which cut-off point provides the most accurate classification, the area under the receiver operating characteristic curve (AUCs), sensitivity and specificity per point were calculated. In total, 215 assessments were included, 62% were performed in boys and the median age was 12.9 years (interquartile range: 8.5-15.8). The PED-SARC-F scores correlated moderately with the measurements of muscle strength (r(s) = -0.37 to -0.47, p < 0.001) and physical performance (r(s) = -0.45 to -0.66, p < 0.001), and weakly with ASMM (r(s) = -0.27, p < 0.001). The PED-SARC-F had an AUC of 0.90 (95% confidence interval (CI) = 0.84-0.95) for functional sarcopenia and 0.79 (95% CI = 0.68-0.90) for structural sarcopenia. A cut-off point of >= 5 had the highest specificity of 96% and a sensitivity of 74%.In conclusion, we adapted the SARC-F to a pediatric version, confirmed its excellent diagnostic accuracy for identifying functional sarcopenia and defined a clinically useful cut-off point in pediatric hemato-oncology patients. Show less
Hulst, A.M. van; Akker, E.L.T. van den; Verwaaijen, E.J.; Fiocco, M.; Rensen, N.; Litsenburg, R.R.L. van; ... ; Heuvel‐Eibrink, M.M. van den 2023
Background: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic... Show moreBackground: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contem-porary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. Method and patients: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Informa-tion on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. Results: Newly diagnosed patients with ALL (n Z 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence in-terval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. Conclusion: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. Show less
Brigitha, L.J.; Fiocco, M.; Pieters, R.; Albertsen, B.K.; Escherich, G.; Lopez-Lopez, E.; ... ; Ponte di Legno Toxicity Working Group 2022
Background: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic... Show moreBackground: Hypersensitivity reactions to asparaginase challenge its use and occur frequently (30-75%) after native Escherichia Coli (E.coli) asparaginase. Comparison of inci-dence of allergic reactions to pegylated E.coli asparaginase (PEGasparaginase) across contem-porary paediatric acute lymphoblastic leukaemia (ALL) protocols is lacking. Method and patients: Questionnaires were sent to all members of the international ALL Ponte di Legno Toxicity Working Group. Meta-analyses were conducted to estimate the incidence of three types of hypersensitivity (allergy, allergic-like reaction and silent inactivation). Informa-tion on protocol level regarding PEGasparaginase dosing regimen, administration route and use of therapeutic drug monitoring was collected for risk analysis. Results: Newly diagnosed patients with ALL (n Z 5880), aged 1-24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The incidence of allergic reactions (sum of allergies and allergic-like reactions) [95% confidence in-terval] was 2% [1%; 3%] during induction and 8% [5%; 11%] during postinduction. Route of administration, number of doses, dosage and number of PEGasparaginase-free weeks did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis suggests that initiation of PEGasparaginase in postinduction and higher number of PEGasparaginase-free intervals increased the risk for allergic reactions. 9-16% and 23-29% of all hypersensitivities were allergic-like reactions and silent inactivation, respectively. Conclusion: The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared with that reported for E.coli asparaginase or PEGasparaginase after E.coli asparaginase. Postinduction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in postinduction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. Show less
Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes.... Show moreGenomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using molecular inversion probe sequencing and breakpoint-spanning polymerase chain reaction analysis we reliably detected alterations with an allele frequency below 1%. We identified 660 genomic alterations in 285 diagnostic samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment. Show less
Binsbergen, A.L.; Haas, V.; Velden, V.H.J.; Groot-Kruseman, H.A.; Fiocco, M.; Pieters, R. 2021
Background: Children with acute lymphoblastic leukemia (ALL) and high-risk (HR) features have a poor outcome and are treated with HR blocks, often followed by allogenic stem cell transplantation ... Show moreBackground: Children with acute lymphoblastic leukemia (ALL) and high-risk (HR) features have a poor outcome and are treated with HR blocks, often followed by allogenic stem cell transplantation (SCT). Procedure: This article analyses the outcomes of children treated with HR blocks between 2004 and 2017 according to DCOG ALL10/11 protocols. 1297 patients with newly diagnosed ALL were consecutively enrolled, of which 107 met the HR criteria (no complete remission; minimal residual disease (MRD) > 10(-3) after consolidation; "MLL-AF4" translocation and in ALL-10 also poor prednisone response). Patients were treated with one induction and consolidation course followed by three HR chemotherapy blocks, after which they received either SCT or further chemotherapy. MRD levels were measured at end of induction, consolidation, and after each HR block. Results: At five years, the event-free survival was 72.8% (95% CI, 64.6-82.0), and the cumulative incidence of relapse was 13.0% (95% CI, 6.3-19.8). Patients with only negative or low-positive MRD levels during HR blocks had a significantly lower five-year cumulative incidence of relapse (CIR) of 2.2% (95% CI, 0-6.6) compared with patients with one or more high-positive MRD levels (CIR 15.4%; 95% CI, 3.9-26.9). During the entire treatment protocol, 11.2% of patients died due to toxicity. Conclusions: The high survival with HR blocks seems favorable compared with other studies. However, the limit of treatment intensification might have been reached as the number of patients dying from leukemia relapse is about equal as the number of patients dying from toxicity. Patients with negative or low MRD levels during HR blocks have lower relapse rates. Show less
Michels, N.; Boer, J.M.; Enshaei, A.; Sutton, R.; Heyman, M.; Ebert, S.; ... ; Boer, M.L. den 2021
Background Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations ... Show moreBackground Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome.Method Patients (aged 1-23 years) with Down syndrome and acute lymphocytic leukaemia and matched non-Down syndrome patients with acute lymphocytic leukaemia (matched controls) from eight trials (DCOG ALL10 and ALL11, ANZCHOG ALL8, AIEOP-BFM ALL2009, UKALL2003, NOPHO ALL2008, CoALL 07-03, and CoALL 08-09) done between 2002 and 2018 across various countries (the Netherlands, the UK, Australia, Denmark, Finland, Iceland, Norway, Sweden, and Germany) were included. Participants were matched (1:3) for clinical risk factors and genetics, including IKZF1 deletion. The primary endpoint was the comparison of MRD levels (absolute MRD levels were categorised into two groups, low [<0.0001] and high [>= 0.0001]) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls, and the secondary outcomes were comparison of long-term outcomes (event-free survival, overall survival, relapse, and treatment-related mortality [TRM]) between patients with Down syndrome and acute lymphocytic leukaemia and matched controls. Two matched cohorts were formed: for MRD analyses and for long-term outcome analyses. For both cohorts, matching was based on induction regimen; for the long-term outcome cohort, matching also included MRD-guided treatment group. We used mixed-effect models, Cox models, and competing risk for statistical analyses.Findings Of 251 children and adolescents with Down syndrome and acute lymphocytic leukaemia, 136 were eligible for analyses and matched to 407 (of 8426) non-Down syndrome patients with acute lymphocytic leukaemia (matched controls). 113 patients with Down syndrome and acute lymphocytic leukaemia were excluded from matching in accordance with predefined rules, no match was available for two patients with Down syndrome and acute lymphocytic leukaemia. The proportion of patients with high MRD at the end of induction treatment was similar for patients with Down syndrome and acute lymphocytic leukaemia (52 [38%] of 136) and matched controls (157 [39%] of 403; OR 0.97 [95% CI 0.64-1.46]; p=0.88). Patients with Down syndrome and acute lymphocytic leukaemia had a higher relapse risk than did matched controls in the IKZF1 deleted group (relapse at 5 years 37.1% [17.1-57.2] vs 13.2% [6.1-23.1]; cause-specific hazard ratio [HR cs] 4.3 [1.6-11.0]; p=0.0028), but not in the IKZF1 wild-type group (relapse at 5 years 5.8% [2.1-12.2] vs 8.1% [5.1-12.0]; HR cs 1.0 [0.5-2.1]; p=0.99). In addition to increased induction deaths (15 [6%] of 251 vs 69 [0.8%] of 8426), Down syndrome and acute lymphocytic leukaemia was associated with a higher risk of post-induction TRM compared with matched controls (TRM at 5 years 12.2% [7.0-18.9] vs 2.7% [1.3-4.9]; HR cs 5.0 [2.3-10.8]; p<0.0001).Interpretation Induction treatment is equivalently effective for patients with Down syndrome and acute lymphocytic leukaemia and for matched patients without Down syndrome. Down syndrome itself provides an additional risk in individuals with IKZF1 deletions, suggesting an interplay between the germline environment and this poor risk somatic aberration. Different treatment strategies are warranted considering both inherent risk of relapse and high risk of TRM. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Hulst, A.M. van; Verwaaijen, E.J.; Fiocco, M.; Pluijm, S.M.F.; Grootenhuis, M.A.; Pieters, R.; ... ; Heuvel-Eibrink, M.M. van den 2021
Background: Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by... Show moreBackground: Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care.Methods: In a national center setting, pediatric ALL patients between 3 and 18 years are enrolled in an Identification study, which identifies patients with clinically relevant dexamethasone-induced neurobehavioral side effects using the Strengths and Difficulties Questionnaire (SDQ). Contributing factors, such as genetic susceptibility, dexamethasone pharmacokinetics as well as psychosocial and family factors are studied to determine their influence in the inter-patient variability for developing dexamethasone-induced neurobehavioral side effects.Patients with clinically relevant problems (i.e. a rise of >= 5 points on the SDQ Total Difficulties Score after 5 days of dexamethasone) are subsequently included in a randomized double-blind placebo-controlled trial with a cross-over design. They receive two courses placebo followed by two courses hydrocortisone during dexamethasone treatment, or vice versa, each time at least 16 days without study medication in between. The primary endpoint is change in SDQ score. The secondary endpoints are sleep (measured with actigraphy and the Sleep Disturbance Scale for Children) and HRQoL (Pediatric Quality of Life Questionnaire).Discussion: The results of our current study may contribute to the management of future ALL patients who experience dexamethasone-induced neuropsychological problems as it may improve HRQoL for patients who suffer most from dexamethasone-induced neurobehavioral side effects. Furthermore, by investigating multiple risk factors that could be related to inter-patient variability in developing these side effects, we might be able to identify and treat patients who are at risk earlier during treatment. Show less
Hulst, A.M. van; Verwaaijen, E.J.; Fiocco, M.F.; Pluijm, S.M.F.; Grootenhuis, M.A.; Pieters, R.; ... ; Heuvel-Eibrink, M.M. van den 2021
Background: Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by... Show moreBackground: Dexamethasone, a highly effective drug in treating pediatric acute lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects. These side effects are experienced by patients and parents as detrimental with respect to health related quality of life (HRQoL). Based on previous studies, it has been suggested that neurobehavioral side effects are associated to cortisol depletion of the mineralocorticoid receptor in the brain. Our previously reported randomized controlled trial, the Dexadagen study (NTR3280), suggests that physiological hydrocortisone addition during dexamethasone treatment may overcome clinically relevant neurobehavioral problems in patients who experience these problems during dexamethasone treatment. With our current study, we aim to replicate these results in a targeted larger sample before further implementing this intervention into standard of care.Methods: In a national center setting, pediatric ALL patients between 3 and 18 years are enrolled in an Identification study, which identifies patients with clinically relevant dexamethasone-induced neurobehavioral side effects using the Strengths and Difficulties Questionnaire (SDQ). Contributing factors, such as genetic susceptibility, dexamethasone pharmacokinetics as well as psychosocial and family factors are studied to determine their influence in the inter-patient variability for developing dexamethasone-induced neurobehavioral side effects.Patients with clinically relevant problems (i.e. a rise of >= 5 points on the SDQ Total Difficulties Score after 5 days of dexamethasone) are subsequently included in a randomized double-blind placebo-controlled trial with a cross-over design. They receive two courses placebo followed by two courses hydrocortisone during dexamethasone treatment, or vice versa, each time at least 16 days without study medication in between. The primary endpoint is change in SDQ score. The secondary endpoints are sleep (measured with actigraphy and the Sleep Disturbance Scale for Children) and HRQoL (Pediatric Quality of Life Questionnaire).Discussion: The results of our current study may contribute to the management of future ALL patients who experience dexamethasone-induced neuropsychological problems as it may improve HRQoL for patients who suffer most from dexamethasone-induced neurobehavioral side effects. Furthermore, by investigating multiple risk factors that could be related to inter-patient variability in developing these side effects, we might be able to identify and treat patients who are at risk earlier during treatment. Show less
Atteveld, J.E. van; Groot-Kruseman, H.A. de; Fiocco, M.; Lequin, M.H.; Neggers, S.J.C.M.M.; Pluijm, S.M.F.; ... ; Heuvel-Eibrink, M.M. van den 2021
Background: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic... Show moreBackground: ABL-class fusion genes other than BCR-ABL1 have been identified in approximately 3% of children with newly diagnosed acute lymphocytic leukaemia, and studies suggest that leukaemic cells carrying ABL-class fusions can be targeted successfully by tyrosine-kinase inhibitors. We aimed to establish the baseline characteristics and outcomes of paediatric patients with ABL-class fusion B-cell acute lymphocytic leukaemia in the pre-tyrosine-kinase inhibitor era.Methods: This multicentre, retrospective, cohort study included paediatric patients (aged 1-18 years) with newly diagnosed ABL-class fusion (ABL1 fusion-positive, ABL2 fusion-positive, CSF1R fusion-positive, and PDGFRB fusion-positive) B-cell acute lymphocytic leukaemia enrolled in clinical trials of multidrug chemotherapy done between Oct 3, 2000, and Aug 28, 2018, in which tyrosine-kinase inhibitors had not been given as a first-line treatment. Patients from 14 European, North American, and Asia-Pacific study groups of the Ponte di Legno group were included. No patients were excluded, and patients were followed up by individual study groups. Through the Ponte di Legno group, we collected data on the baseline characteristics of patients, including IKZF1, PAX5, and CDKN2A/B deletion status, and whether haematopoietic stem cell transplantation (HSCT) had been done, as well as treatment outcomes, including complete remission, no response, relapse, early death, and treatment-related mortality, response to prednisone, and minimal residual disease (MRD) at end of induction therapy. 5-year event-free survival and 5-year overall survival were estimated by use of Kaplan-Meier methods, and the 5-year cumulative incidence of relapse was calculated by use of a competing risk model.Findings: We identified 122 paediatric patients with newly diagnosed ABL-class fusion B-cell acute lymphocytic leukaemia (77 from European study groups, 25 from North American study groups, and 20 from Asia-Pacific study groups). 64 (52%) of 122 patients were PDGFRB fusion-positive, 40 (33%) were ABL1 fusion-positive, ten (8%) were CSF1R fusion-positive, and eight (7%) were ABL2 fusion-positive. In all 122 patients, 5-year event-free survival was 59.1% (95% CI 50.5-69.1), 5-year overall survival was 76.1% (68.6-84.5), and the 5-year cumulative incidence of relapse was 31.0% (95% CI 22.4-40.1). MRD at the end of induction therapy was high (>= 10(-2) cells) in 61 (66%) of 93 patients, and most prevalent in patients with ABL2 fusions (six [86%] of 7 patients) and PDGFRB fusion-positive B-cell acute lymphocytic leukaemia (43 [88%] of 49 patients). MRD at the end of induction therapy of 10(-2) cells or more was predictive of an unfavourable outcome (hazard ratio of event-free survival in patients with a MRD of >= 10(-2) vs those with a MRD of <10(-2) 3.33 [95% CI 1.46-7.56], p=0.0039). Of the 36 (30%) of 119 patients who relapsed, 25 (69%) relapsed within 3 years of diagnosis. The 5-year cumulative incidence of relapse in 41 patients who underwent HSCT (17.8% [95% CI 7.7-31.3]) was lower than in the 43 patients who did not undergo HSCT (45.1% [28.4-60.5], p=0.013), but event-free survival and overall survival did not differ between these two groups.Interpretation: Children with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
Oosterom, N.; Fiocco, M.; Kloos, R.Q.H.; Sluis, I.M. van der; Pieters, R.; Zelst, B.D. van; ... ; Heil, S.G. 2020
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.... Show moreBackground 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/m(2)/dose) and Leucovorin (15 mg/m(2)/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-PG(2-5)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 3(d)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 3(d)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. Show less
Genomic alterations in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may provide insight into the role of specific genomic events in relapse development. Along this line,... Show moreGenomic alterations in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may provide insight into the role of specific genomic events in relapse development. Along this line, comparisons between the spectrum of alterations in relapses that arise in different upfront treatment protocols may provide valuable information on the association between the tumor genome, protocol components and outcome. Here, we performed a comprehensive characterization of relapsed BCP-ALL cases that developed in the context of 3 completed Dutch upfront studies, ALL8, ALL9, and ALL10. In total, 123 pediatric BCP-ALL relapses and 77 paired samples from primary diagnosis were analyzed for alterations in 22 recurrently affected genes. We found pronounced differences in relapse alterations between the 3 studies. Specifically, CREBBP mutations were observed predominantly in relapses after treatment with ALL8 and ALL10 which, in the latter group, were all detected in medium risk-treated patients. IKZF1 alterations were enriched 2.2-fold (p = 0.01) and 2.9-fold (p < 0.001) in ALL8 and ALL9 relapses compared to diagnosis, respectively, whereas no significant enrichment was found for relapses that were observed after treatment with ALL10. Furthermore, IKZF1 deletions were more frequently preserved from a major clone at diagnosis in relapses after ALL9 compared to relapses after ALL8 and ALL10 (p = 0.03). These data are in line with previous studies showing that the prognostic value of IKZF1 deletions differs between upfront protocols and is particularly strong in the ALL9 regimen. In conclusion, our data reveal a correlation between upfront treatment and the genetic composition of relapsed BCP-ALL. Show less
Klaassen, I.L.M.; Lauw, M.N.; Fiocco, M.; Sluis, I.M. van der; Pieters, R.; Middeldorp, S.; ... ; Ommen, C.H. van 2019
