Annelienke van Hulst

Towards beating dexamethasone-induced side effects in children with acute lymphoblastic leukemia Annelienke M. van Hulst

Towards Beating Dexamethasone-Induced Side Effects in Children with Acute Lymphoblastic Leukemia Annelienke M. van Hulst

Copyright 2023 © A.M. van Hulst The Netherlands. All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission of the author. ISBN: 978-94-6483-289-1 Provided by thesis specialist Ridderprint, Printing: Ridderprint Cover design and layout: © The research described in this thesis was performed at the Princess Máxima Center for Pediatric Oncology (Utrecht, The Netherlands) and financially supported by Stichting Kinderen Kankervrij (Foundation KiKa), grant number 268. Printing of this thesis was financially supported by the SBOH.

Towards Beating Dexamethasone-Induced Side Effects in Children with Acute Lymphoblastic Leukemia Op Weg naar het Overwinnen van Dexamethason-Geïnduceerde Bijwerkingen bij Kinderen met Acute Lymfatische Leukemie (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. H.R.B.M. Kummeling, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 30 november 2023 des middags te 12.15 uur door Annelienke Michelle van Hulst geboren op 14 februari 1990 te Amersfoort

Promotoren: Prof. dr. M.M. van den Heuvel-Eibrink Prof. dr. M.A. Grootenhuis Prof. dr. E.L.T. van den Akker Beoordelingscommissie: Prof. dr. A.L. van Baar Prof. dr. O.C. Meijer Dr. H.M. van Santen Prof. dr. H.J. Vormoor (voorzitter) Prof. dr. M.J.E. van Zandvoort

“It’s the repetition of affirmations that leads to belief. And once that belief becomes a deep conviction, things begin to happen.” - Muhammad Ali

CONTENT Chapter 1 General introduction 9 Chapter 2 Risk factors for steroid-induced adverse psychological reactions and sleep problems in pediatric acute lymphoblastic leukemia: A systematic review Psycho-Oncology. 2021 Jul;30(7):1009-1028 29 Chapter 3 Study protocol: DexaDays-2, hydrocortisone for treatment of dexamethasone-induced neurobehavioral side effects in pediatric leukemia patients: a double-blind placebo controlled randomized intervention study with cross-over design BioMed Central Pediatrics. 2021 Sep;21(1):427-435 97 Chapter 4 Unraveling Dexamethasone-Induced Neurobehavioral and Sleep Problems in Children With ALL: Which Determinants Are Important? Journal of Clinical Oncology – Precision Oncology. 2023 Jun;7 :e2200678 117 Chapter 5 Leptin increase during dexamethasone and its association with hunger and fat, in pediatric acute lymphoblastic leukemia Under review 153 Chapter 6 Hydrocortisone to reduce dexamethasone-induced neurobehavioral side-effects in children with acute lymphoblastic leukemia-results of a double-blind, randomized controlled trial with cross-over design European Journal of Cancer. 2023 Apr;187:124-133 177 Chapter 7 The role of the mineralocorticoid receptor in steroid-induced cytotoxicity in pediatric acute lymphoblastic leukemia Under review 221 Chapter 8 General discussion and future perspectives 247 Addendum English summary 273 Nederlandse samenvatting 279 About the author 285 List of publications 289 PhD portfolio 295 Dankwoord 301

General introduction

11 General introduction 1 ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer type, with approximately 120 new patients each year in The Netherlands.1 This hematologic malignancy originates from the bone marrow, where under normal circumstances hematopoietic stem cells produce all lineages of blood and immune cells (Figure 1). In ALL, normal hematopoiesis is interrupted by maturation arrest of one of the lymphatic cell lines, followed by uncontrolled growth of malignant immature monoclonal lymphoid cells. This expansion of leukemic cells leads to a decreased production of erythrocytes, platelets and functional leukocytes.2 Both precursor B-cell and T-cell leukemia can occur in children, with precursor B-cell ALL being the most common variant (85%). The peak incidence of ALL in children is between the age of two and five years and boys are slightly more often affected than girls.1 Figure 1. Normal hematopoiesis

12 Chapter 1 TREATMENT AND SURVIVAL Survival of ALL has increased tremendously over the past decades. In high-income countries, the five-year event free survival rose from around 35% in the 1970’s to more than 90% in current treatment protocols (Figure 2).3,4 This improvement was due to optimization of chemotherapy regimens as well as improved response based risk stratification and supportive care. From 2011 to 2020, children with ALL were treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, and the studies described in this thesis were all conducted under this protocol. Cum Overall Survival 1,0 0,8 0,6 0,4 0,2 0,0 time (years) 40 35 30 25 20 15 10 5 0 … DCLSG-ALL1 (1972-1973) DCLSG-ALL2 (1973-1975) DCLSG-ALL3/ALL4 (1975-1978) DCLSG-ALL5 (1978-1983) DCLSG-ALL6 (1983-1988) DCLSG-ALL7 (1988-1991) DCLSG-ALL8 (1991-1997) DCLSG-ALL9/INTERFANT99 (1998-2004) DCOG-ALL10/INTERFANT06/ESPHALL (2004-2012) DCOG-ALL11/INTERFANT06/ESPHALL (2012-2020) Figure 2. DCOG Registration: Outcome ALL 1997-2020 by protocol period Courtesy dr. H. de Groot-Kruseman Treatment in ALL-11 consisted of four phases: induction, consolidation, intensification and maintenance. During induction treatment, patients received high doses chemotherapy and prednisolone. The intensity of treatment after induction therapy was based on therapy response and specific chromosomal abnormalities. In the ALL-11 protocol, patients were stratified to standard, medium or high risk treatment. Medium risk (MR) maintenance treatment plays a key role in this thesis. MR maintenance treatment contained 28 three weekly treatment cycles. Patients received doxorubicin on the first day of the first four treatment cycles, vincristine once every three weeks, methotrexate once per week and 6-mercaptopurine once per day, as well as dexamethasone for five consecutive days at the beginning of each treatment cycle (Figure 3). Depending on randomization, patients also received asparaginase once every three weeks until week 15 or 27 of maintenance treatment. Apart from curative treatment and associated supportive care, standard care includes systematic psychosocial support for both the child and family, support from social work and physical activity recommendations.

13 General introduction 1 Week 1 2 3 4 5 Dexamethasone 6 mg/m2/day po Vincristine 2 mg/m2/dose iv Methotrexate 30 mg/m2/dose iv 6-Mercaptopurine 50mg/m2/day po Doxorubicin till week 11 Asparaginase till week 15 or 27 Figure 3. ALL-11 medium risk maintenance treatment schedule

14 Chapter 1 CORTICOSTEROIDS Glucocorticoids, such as dexamethasone and prednisone, are important components in the treatment of ALL. Glucocorticoids regulate numerous biological processes such as metabolism, immunity, inflammation and the stress response.5 Mineralocorticoids, such as aldosterone, are another corticosteroid type, which regulate electrolyte and fluid balance.5 The naturally occurring glucocorticoid in humans is cortisol, which is produced by the adrenal cortex and which exerts a negative feedback through the hypothalamicpituitary-adrenal (HPA) axis upon endogenous production (Figure 4).5 Hydrocortisone is the medical equivalent of cortisol and is among others used as substitution therapy for patients who lack endogenous cortisol due to adrenal insufficiency.5 Prednisone and dexamethasone are synthetic glucocorticoids, a drug class that was used as the first treatment of (childhood) leukemia in the late 1940s due to the cytotoxic effect on leukemic cells.6 Prednisone, which first requires hepatic conversion to its biologically active form (prednisolone), was the preferred steroid in the treatment of ALL during many different treatment protocols. However, since the introduction of dexamethasone led to a decrease in central nervous system (CNS) relapses, and a higher event-free survival in most ALL patients, dexamethasone has been increasingly used in current treatment protocols.7-11 Figure 4. Hypothalamic-pituitary-adrenal (HPA) axis

15 General introduction 1 CORTICOSTEROID RECEPTORS AND GLUCOCORTICOID AFFINITY Glucocorticoids can bind and activate two receptor types: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Both are members of the steroid receptor superfamily and are encoded by the NR3C1 and NR3C2 gene respectively. The GR and MR are structurally and functionally related. They are localized in the cytosol and upon ligand binding translocate into the nucleus, where they exert their actions through transcriptional activation or repression.12,13 The MR is expressed in numerous tissues: in epithelial tissues such as the kidney it is aldosterone selective and its main function is sodium and water retention, alongside potassium secretion.14 In other tissues such as heart, muscle, liver and brain, the MR is also present but its function is more complex.12 The GR is expressed in nearly all tissue types and is above all essential in maintaining physiological balance.13 Depending on the expressing tissue, the GR and MR show different affinities for cortisol which can lead to distinct effects.15,16 This effect is influenced by two key enzymes: 11betahydroxysteroid dehydrogenase (11β-HSD) 1 and 11β-HSD 2. 11β-HSD 2 metabolizes cortisol to inactive cortisone, therefore favoring binding of aldosterone to the MR. Conversely, 11β-HSD 1 converts cortisone to the active cortisol. The presence or absence of both enzymes in peripheral tissue mostly determines the effect of corticosteroids on both receptors. Glucocorticoids exert their cytotoxic effect on leukemic cells predominantly through activation of the GR. After binding of glucocorticoids to the GR, the complex is translocated to the nucleus where it can induce cell-cycle arrest and apoptosis through multiple pathways.17-20 Different synthetic glucocorticoids have different affinities for the GR and MR. Conventionally, dexamethasone is reported to be the most potent glucocorticoid with a sevenfold higher glucocorticoid activity than prednisolone, and no mineralocorticoid activity.5 Prednisolone exerts an effect through both receptors, although with higher affinity for the GR.5 However, these reports are based on anti-inflammatory and Na+- retaining potency. In pediatric ALL samples, previous studies showed that the in vitro anti-leukemic (cytotoxic) activity of dexamethasone is seventeen fold higher than prednisolone.21,22 However, different studies, using various models and evaluating diverse effects of glucocorticoids, show wide ranges of glucocorticoid and mineralocorticoid activity when comparing either dexamethasone, prednisolone or hydrocortisone.22-25 The anti-leukemic activity of these glucocorticoids and the role of the GR and MR in this cytotoxic effect therefore remains unclear.

16 Chapter 1 GLUCOCORTICOID-INDUCED SIDE EFFECTS Besides the anti-leukemic effect of dexamethasone and prednisolone, both glucocorticoids can also induce various undesirable side effects. These side effects involve almost every organ system and range from acute side effects, to side effects that become apparent later in life. Overall, dexamethasone is associated with more (severe) side effects than prednisolone.26 Both glucocorticoid-induced adverse psychological reactions and somatic side effects may occur during ALL treatment. Adverse psychological reactions Adverse psychological and neurocognitive reactions due to glucocorticoids may include neurobehavioral problems (e.g. increased distress, compulsive behavior or altered emotions), psychiatric deterioration (e.g. psychosis, depression), cognitive decline, changes in sleep, increased fatigue or preoccupation with food.27-30 All these side effects may potentially impact quality of life during treatment of childhood ALL for both the patient and family, for a substantial period of time, since ALL treatment lasts 2-3 years.31,32 Reports on estimated frequencies of glucocorticoid-induced neurobehavioral problems in children range from 5% to 75%,28,33-36 whereas sleep problems are reported in 19% to 87%.35,37 In this thesis, the emphasis lies on dexamethasone-induced neurobehavioral and sleep problems, as well as the feeling of hunger children experience during dexamethasone treatment. Patients at risk The inter-individual variation in the severity of glucocorticoid-induced side effects is high. For better understanding of this inter-individual variation, more insight in contributing factors that may influence neurobehavioral and sleep problems during dexamethasone treatment would be of value. The risk factors for developing neurobehavioral side effects during dexamethasone treatment are multi-dimensional and therefore gathering insight in the full scope of possible determinants is important. Patient and treatment characteristics In adults (both with and without cancer diagnosis), a higher steroid dose as well as psychiatric history increased the risk of neurobehavioral side effects.38,39. In children, dexamethasone, as compared to prednisolone, as well as a younger age appear to increase the risk of steroid-induced neurobehavioral problems.40,41 Previously established risk factors for sleep problems in healthy children are female sex, a difficult temperament and unhealthy sleep behavior.42 In childhood cancer survivors, female sex, co-morbidities and lower educational level were associated with insomnia.43

17 General introduction 1 Psychosocial and environmental factors It has been previously shown that the child’s distress during procedures in childhood cancer treatment is associated with parental distress and parental stress on its own is associated with behavioral problems in children.44,45 Moreover, parents of a child with cancer appear to have higher stress levels than parents of children with physical disabilities.46 Overall, the degree of parental stress may be a factor in the occurrence of dexamethasone induced behavioral or sleep problems.47 Besides parenting stress, other family or environmental risk factors such as familial predisposition,48 parenting strategies,49-51 or psychosocial support may affect parents’ perceptions of the side effects which occur during dexamethasone. Genetic and pharmacokinetic factors Genetic variation may contribute to the differences in dexamethasone-induced side effects as well, therefore studying single nucleotide polymorphisms (SNPs) which may contribute to differences in neurobehavioral and sleep problems would be of value. Two previous studies suggest an association between the Bcl-1 polymorphism (NR3C1 gene) and depressive symptoms.52,53 The rs4918 polymorphism (Alpha2-HS glycoprotein (AHSG) gene) was suggested to be associated with impaired sleep during dexamethasone treatment in pediatric ALL patients.54 However, replication of these results is still pending. Genetic variants that have been shown to be associated with psychopathology or sleep problems, may give further insight in the pathophysiology and risk of these side effects caused by dexamethasone. In addition, dexamethasone pharmacokinetics may play a role in the occurrence of neurobehavioral side effects. Dexamethasone clearance is higher in younger children, so there may be an inter-patient variability in dexamethasone levels during maintenance phase, which may explain the differences in side effects.55 In summary, many different factors may contribute to the inter-patient variability of both dexamethasone-induced neurobehavioral and sleep problems. Some of these factors have been described before, however, findings are often conflicting or focus on only one possible determinant or outcome. It would be of interest to review the complete literature regarding risk factors for dexamethasone-induced neurobehavioral and sleep problems and to prospectively study these possible determinants. Somatic side effects Somatic side effects of glucocorticoids include increased risk of infections, osteonecrosis, osteopenia and consequent fractures, thromboembolisms, metabolic changes such as hyperglycemia, hyperlipidemia, weight gain, hypertension and myopathy.11,26,56-58 Previous research in children with ALL showed that merely four or five days of dexamethasone

18 Chapter 1 treatment induced metabolic toxicity on three components of the metabolic syndrome as well as significant insulin resistance in 45-85% of all cases.58,59 This implies that the high dose glucocorticoid pulses which are frequently administered in ALL treatment trigger significant metabolic changes. In survivors of childhood ALL, obesity is a well-known late side effect, and glucocorticoid use is an independent risk factor for obesity in survivors.60 Leptin is an adipokine which is mainly produced by adipose tissue, and is among others involved in regulating food intake, which is also disturbed during glucocorticoid treatment.61 The effect of five days of dexamethasone on leptin, fat mass and feeling of hunger has not been studied before. By exploring these acute side effects of dexamethasone, new insights in the pathophysiological mechanisms of important late side effect may arise.

19 General introduction 1 PATHOPHYSIOLOGY OF NEUROBEHAVIORAL SIDE EFFECTS The proposed pathophysiology behind neurobehavioral side effects of glucocorticoids commences in the brain, where both the GR and MR are present. Both receptors are expressed in different areas of the brain: the MR is mostly present in limbic areas whereas the GR is present in nearly every brain region.62,63 Because dexamethasone, through negative feedback on the HPA axis, suppresses the endogenous production of cortisol which has a high affinity for the MR, an imbalance between activation of the GR and MR occurs during high dose dexamethasone treatment.62,64 Dexamethasone-induced neurobehavioral problems may be due to overactivation of the GR, underactivation of the MR or an imbalance between activation of both receptors.65 Still, in animals as well as humans, it has been shown that the MR plays an important role in behavior and cognition. For instance, in MR knockout mice, an increased anxiety behavior has been observed due to the absence of functional MR.66 Conversely, overexpression of MR in the brain of mice resulted in decreased anxiety.67,68 In healthy humans, treatment with the MR antagonist spironolactone has been associated with impaired attention, memory and sleep.69,70 Furthermore, in patients with psychiatric disorders such as depression, schizophrenia or bipolar disorder, a decreased expression of MR in parts of the brain has been established.71,72 In contrast, treatment with MR agonist fludrocortisone showed a beneficial effect as add-on to standard depression treatment.73 The MR therefore may play an important role in the development of dexamethasone-induced neurobehavioral problems.

20 Chapter 1 TREATMENT OF DEXAMETHASONE-INDUCED NEUROBEHAVIORAL PROBLEMS Based on the previously mentioned studies in mice and human, it has been hypothesized that addition of a physiological dose of hydrocortisone during dexamethasone treatment would diminish the neurobehavioral side effects of dexamethasone through refilling of the brain MR.65 This was explored in a randomized clinical trial in 50 pediatric ALL patients: the DexaDays-1 study.35 The safety of addition of a physiological dose of hydrocortisone to dexamethasone treatment was first ensured in a preclinical study, which showed that hydrocortisone did not interfere with the anti-leukemic efficacy of dexamethasone.74 In the total group of pediatric ALL patients, no beneficial effect of hydrocortisone on neurobehavioral or sleep problems was observed (Figure 5). However, in a subgroup of patients with clinically relevant dexamethasone-induced neurobehavioral problems (38%) or clinically relevant sleep problems (19%), hydrocortisone addition showed a significant decrease of the side effects (Figure 5). These results implicated that behavioral and sleep problems may be reduced in children who are most affected. However, despite the significance, since these results were based on a relatively small subgroup, validation in a larger targeted cohort was desired. -30 -20 -10 0 10 20 Effect of hydrocortisone on dexamethasone-induced side effects SDQ SDSC Neurobehavioral problems Sleep problems Total group Clinically significant problems Figure 5. Results of the DexaDays-1 study. The effect of hydrocortisone addition in the total group (blue) and in patients with clinically relevant dexamethasone-induced behavioral (left) or sleep (right) problems (orange). Behavioral problems were measured with the Strengths and Difficulties Questionnaire (SDQ) and sleep problems were measured with the Sleep Disturbance Scale for Children (SDSC). Adapted from Warris et al. Journal of Clinical Oncology 2016.35

21 General introduction 1 SCOPE AND OUTLINE OF THIS THESIS In this thesis, we aim to increase existing knowledge on the prevalence and determinants of dexamethasone-induced side effects in children with ALL. Moreover, we aim to validate the finding that hydrocortisone addition to dexamethasone treatment leads to a significant reduction of clinically relevant dexamethasone-induced neurobehavioral and sleep problems. Furthermore, we aim to describe the role of the mineralocorticoid receptor in steroid-induced cytotoxicity. Chapter 2 provides a systematic review of the literature regarding the risk factors for glucocorticoid-induced neurobehavioral and sleep problems. In Chapter 3, we describe the design of the DexaDays-2 study, which consists of two parts. First, we measured which patients experience clinically relevant dexamethasone-induced neurobehavioral problems. The risk factors for developing these problems are described in Chapter 4. Related somatic effects were studied in this cohort by measuring the influence of a five-day dexamethasone course on leptin levels, fat mass and feeling of hunger (Chapter 5). The core part of the DexaDays-2 study comprised a randomized placebo-controlled trial, which evaluated the beneficial effect of hydrocortisone addition to dexamethasone treatment on neurobehavioral and sleep problems, as well as quality of life. The results of this study are described in Chapter 6. Finally, in addition to studying glucocorticoid related side effects in children with ALL, in Chapter 7 we describe our study that was designed to get insight into biological mechanisms of the in vitro effect of various steroids on glucocorticoidinduced cytotoxicity through glucocorticoid and mineralocorticoid receptor activation.

22 Chapter 1 REFERENCES 1. SKION. Kinderoncologie in cijfers. SKION Basisregistratie. Retrieved from: info/4208/kinderoncologie-in-cijfers/, 2. Sachs L: The control of hematopoiesis and leukemia: from basic biology to the clinic. Proc Natl Acad Sci U S A 93:4742-9, 1996 3. Inaba H, Mullighan CG: Pediatric acute lymphoblastic leukemia. Haematologica 105:2524-2539, 2020 4. Kamps WA, van der Pal-de Bruin KM, Veerman AJ, et al: Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004. Leukemia 24:309-19, 2010 5. Schimmer BP, Funder JW: Adrenocorticotropic Hormone, Adrenal Steroids, and the Adrenal Cortex, in Brunton LL, Hilal-Dandan R, Knollmann BC (eds): Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. New York, NY, McGraw-Hill Education, 2017 6. Pearson OH, Eliel LP: Use of pituitary adrenocorticotropic hormone (ACTH) and cortisone in lymphomas and leukemias. J Am Med Assoc 144:1349-53, 1950 7. Inaba H, Pui CH: Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol 11:1096-106, 2010 8. Bostrom BC, Sensel MR, Sather HN, et al: Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood 101:3809-17, 2003 9. Reedijk AMJ, Coebergh JWW, de Groot-Kruseman HA, et al: Progress against childhood and adolescent acute lymphoblastic leukaemia in the Netherlands, 1990-2015. Leukemia 35:1001-1011, 2021 10. Veerman AJ, Kamps WA, van den Berg H, et al: Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncol 10:957-66, 2009 11. Vrooman LM, Stevenson KE, Supko JG, et al: Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study--DanaFarber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol 31:1202-10, 2013 12. Grossmann C, Almeida-Prieto B, Nolze A, et al: Structural and molecular determinants of mineralocorticoid receptor signalling. Br J Pharmacol 179:3103-3118, 2022 13. Kadmiel M, Cidlowski JA: Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci 34:518-30, 2013 14. Ronzaud C, Loffing J, Bleich M, et al: Impairment of sodium balance in mice deficient in renal principal cell mineralocorticoid receptor. J Am Soc Nephrol 18:1679-87, 2007 15. Baker ME, Funder JW, Kattoula SR: Evolution of hormone selectivity in glucocorticoid and mineralocorticoid receptors. J Steroid Biochem Mol Biol 137:57-70, 2013 16. Koning A, Buurstede JC, van Weert L, et al: Glucocorticoid and Mineralocorticoid Receptors in the Brain: A Transcriptional Perspective. J Endocr Soc 3:1917-1930, 2019 17. Harmon JM, Norman MR, Fowlkes BJ, et al: Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line. J Cell Physiol 98:267-78, 1979 18. Jia WY, Zhang JJ: Effects of glucocorticoids on leukocytes: Genomic and non-genomic mechanisms. World J Clin Cases 10:7187-7194, 2022

23 General introduction 1 19. Wyllie AH: Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284:555-6, 1980 20. Haarman EG, Kaspers GJ, Veerman AJ: Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation. Br J Haematol 120:919-29, 2003 21. Kaspers GJL, Veerman AJP, PoppSnijders C, et al: Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Medical and Pediatric Oncology 27:114-121, 1996 22. Styczynski J, Wysocki M, Balwierz W, et al: In vitro comparative antileukemic activity of various glucocorticoids in childhood acute leukemia. Neoplasma 49:178-83, 2002 23. Ito C, Evans WE, McNinch L, et al: Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol 14:2370-6, 1996 24. Grossmann C, Scholz T, Rochel M, et al: Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol 151:397-406, 2004 25. Kaspers GJ, Veerman AJ, Popp-Snijders C, et al: Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med Pediatr Oncol 27:114-21, 1996 26. Teuffel O, Kuster SP, Hunger SP, et al: Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Leukemia 25:1232-8, 2011 27. Felder-Puig RS, C.; Baumgartner, M.; Ortner, M.; Aschenbrenner, C.; Bieglmayer, C.; Voigtlander, T.; Panzer-Grumayer, E. R.; Tissing, W. J.; Koper, J. W.; Steinberger, K.; Nasel, C.; Gadner, H.; Topf, R.; Dworzak, M.: Glucocorticoids in the treatment of children with acute lymphoblastic leukemia and hodgkin’s disease: a pilot study on the adverse psychological reactions and possible associations with neurobiological, endocrine, and genetic markers. Clin Cancer Res 13:7093-100, 2007 28. Stuart FA, Segal TY, Keady S: Adverse psychological effects of corticosteroids in children and adolescents. Arch Dis Child 90:500-6, 2005 29. Warris LT, van den Akker ELT, Bierings MB, et al: Eating behavior during dexamethasone treatment in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 64, 2017 30. Rogers VE, Zhu S, Ancoli-Israel S, et al: Impairment in circadian activity rhythms occurs during dexamethasone therapy in children with leukemia. Pediatr Blood Cancer 61:1986-91, 2014 31. Fardell JE, Vetsch J, Trahair T, et al: Health-related quality of life of children on treatment for acute lymphoblastic leukemia: A systematic review. Pediatr Blood Cancer 64, 2017 32. McGrath P, Pitcher L: ‘Enough is enough’: qualitative findings on the impact of dexamethasone during reinduction/consolidation for paediatric acute lymphoblastic leukaemia. Support Care Cancer 10:146-55, 2002 33. Aljebab F, Choonara I, Conroy S: Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in Children. PLoS One 12:e0170259, 2017 34. Hochhauser CJ, Lewis M, Kamen BA, et al: Steroid-induced alterations of mood and behavior in children during treatment for acute lymphoblastic leukemia. Support Care Cancer 13:967-74, 2005 35. Warris LT, van den Heuvel-Eibrink MM, Aarsen FK, et al: Hydrocortisone as an Intervention for Dexamethasone-Induced Adverse Effects in Pediatric Patients With Acute Lymphoblastic Leukemia: Results of a Double-Blind, Randomized Controlled Trial. J Clin Oncol 34:2287-93, 2016

24 Chapter 1 36. Warris LT, van den Heuvel-Eibrink MM, den Hoed MA, et al: Does dexamethasone induce more neuropsychological side effects than prednisone in pediatric acute lymphoblastic leukemia? A systematic review. Pediatr Blood Cancer 61:1313-8, 2014 37. Zupanec S, Jones H, Stremler R: Sleep Habits and Fatigue of Children Receiving Maintenance Chemotherapy for ALL and Their Parents. Journal of Pediatric Oncology Nursing 27:217-228, 2010 38. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther 13:694-8, 1972 39. Fardet L, Petersen I, Nazareth I: Suicidal behavior and severe neuropsychiatric disorders following glucocorticoid therapy in primary care. Am J Psychiatry 169:491-7, 2012 40. Drozdowicz LB, Bostwick JM: Psychiatric Adverse Effects of Pediatric Corticosteroid Use. Mayo Clinic Proceedings 89:817-834, 2014 41. Mrakotsky CM, Silverman LB, Dahlberg SE, et al: Neurobehavioral side effects of corticosteroids during active treatment for acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. Pediatr Blood Cancer 57:4928, 2011 42. Belmon LS, van Stralen MM, Busch V, et al: What are the determinants of children’s sleep behavior? A systematic review of longitudinal studies. Sleep Med Rev 43:60-70, 2019 43. Peersmann SHM, Grootenhuis MA, van Straten A, et al: Insomnia Symptoms and Daytime Fatigue Co-Occurrence in Adolescent and Young Adult Childhood Cancer Patients in Follow-Up after Treatment: Prevalence and Associated Risk Factors. Cancers (Basel) 14, 2022 44. Caes L, Goubert L, Devos P, et al: The relationship between parental catastrophizing about child pain and distress in response to medical procedures in the context of childhood cancer treatment: a longitudinal analysis. J Pediatr Psychol 39:677-86, 2014 45. Neece CL, Green SA, Baker BL: Parenting stress and child behavior problems: a transactional relationship across time. Am J Intellect Dev Disabil 117:48-66, 2012 46. Hung JW, Wu YH, Yeh CH: Comparing stress levels of parents of children with cancer and parents of children with physical disabilities. Psychooncology 13:898-903, 2004 47. van der Geest IM, van den Heuvel-Eibrink MM, Passchier J, et al: Parenting stress as a mediator of parents’ negative mood state and behavior problems in children with newly diagnosed cancer. Psychooncology 23:758-65, 2014 48. Hamilton JL, Ladouceur CD, Silk JS, et al: Higher Rates of Sleep Disturbance Among Offspring of Parents With Recurrent Depression Compared to Offspring of Nondepressed Parents. J Pediatr Psychol 45:1-11, 2020 49. McCarthy MC, Bastiani J, Williams LK: Are parenting behaviors associated with child sleep problems during treatment for acute lymphoblastic leukemia? Cancer Med 5:1473-80, 2016 50. Rensen N, Steur LMH, Grootenhuis MA, et al: Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: Effects of treatment intensity and dexamethasone pulses. Pediatr Blood Cancer 67:e28697, 2020 51. Williams LK, Lamb KE, McCarthy MC: Behavioral side effects of pediatric acute lymphoblastic leukemia treatment: the role of parenting strategies. Pediatr Blood Cancer 61:2065-70, 2014 52. Spijker AT, van Rossum EF: Glucocorticoid receptor polymorphisms in major depression. Focus on glucocorticoid sensitivity and neurocognitive functioning. Ann N Y Acad Sci 1179:199-215, 2009 53. Kaymak Cihan M, Karabulut HG, Yurur Kutlay N, et al: Association Between N363S and BclI Polymorphisms of the Glucocorticoid Receptor Gene (NR3C1) and Glucocorticoid Side Effects During Childhood Acute Lymphoblastic Leukemia Treatment. Turk J Haematol 34:151-158, 2017

25 General introduction 1 54. Vallance K, Liu W, Mandrell BN, et al: Mechanisms of dexamethasone-induced disturbed sleep and fatigue in paediatric patients receiving treatment for ALL. Eur J Cancer 46:1848-55, 2010 55. Yang L, Panetta JC, Cai X, et al: Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol 26:1932-9, 2008 56. Koltin D, Sung L, Naqvi A, et al: Medication induced diabetes during induction in pediatric acute lymphoblastic leukemia: prevalence, risk factors and characteristics. Support Care Cancer 20:2009-15, 2012 57. Schmiegelow K, Muller K, Mogensen SS, et al: Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res 6:444, 2017 58. Warris LT, van den Akker EL, Bierings MB, et al: Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone. PLoS One 11:e0158225, 2016 59. Chow EJ, Pihoker C, Friedman DL, et al: Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 60:621-6, 2013 60. Pluimakers VG, van Waas M, Neggers S, et al: Metabolic syndrome as cardiovascular risk factor in childhood cancer survivors. Crit Rev Oncol Hematol 133:129-141, 2019 61. Misch M, Puthanveetil P: The Head-to-Toe Hormone: Leptin as an Extensive Modulator of Physiologic Systems. Int J Mol Sci 23, 2022 62. de Kloet ER: From receptor balance to rational glucocorticoid therapy. Endocrinology 155:275469, 2014 63. Reul JM, de Kloet ER: Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology 117:2505-11, 1985 64. Sapolsky RM, Romero LM, Munck AU: How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21:55-89, 2000 65. Meijer OC, de Kloet ER: A Refill for the Brain Mineralocorticoid Receptor: The Benefit of Cortisol Add-On to Dexamethasone Therapy. Endocrinology 158:448-454, 2017 66. Gass P, Reichardt HM, Strekalova T, et al: Mice with targeted mutations of glucocorticoid and mineralocorticoid receptors: models for depression and anxiety? Physiol Behav 73:811-25, 2001 67. Rozeboom AM, Akil H, Seasholtz AF: Mineralocorticoid receptor overexpression in forebrain decreases anxiety-like behavior and alters the stress response in mice. Proc Natl Acad Sci U S A 104:4688-93, 2007 68. Lai M, Horsburgh K, Bae SE, et al: Forebrain mineralocorticoid receptor overexpression enhances memory, reduces anxiety and attenuates neuronal loss in cerebral ischaemia. Eur J Neurosci 25:1832-42, 2007 69. Otte C, Moritz S, Yassouridis A, et al: Blockade of the mineralocorticoid receptor in healthy men: effects on experimentally induced panic symptoms, stress hormones, and cognition. Neuropsychopharmacology 32:232-8, 2007 70. Kellner M, Wiedemann K: Mineralocorticoid receptors in brain, in health and disease: possibilities for new pharmacotherapy. Eur J Pharmacol 583:372-8, 2008 71. Klok MD, Alt SR, Irurzun Lafitte AJ, et al: Decreased expression of mineralocorticoid receptor mRNA and its splice variants in postmortem brain regions of patients with major depressive disorder. J Psychiatr Res 45:871-8, 2011 72. ter Heegde F, De Rijk RH, Vinkers CH: The brain mineralocorticoid receptor and stress resilience. Psychoneuroendocrinology 52:92-110, 2015

26 Chapter 1 73. Otte C, Hinkelmann K, Moritz S, et al: Modulation of the mineralocorticoid receptor as add-on treatment in depression: a randomized, double-blind, placebo-controlled proof-of-concept study. J Psychiatr Res 44:339-46, 2010 74. Warris LT, van den Heuvel-Eibrink MM, Aries IM, et al: Hydrocortisone does not influence glucocorticoid sensitivity of acute lymphoblastic leukemia cells. Haematologica 100:e137-9, 2015


Risk factors for steroid-induced adverse psychological reactions and sleep problems in pediatric acute lymphoblastic leukemia: A systematic review Annelienke M. van Hulst*, Shosha H. M. Peersmann*, Erica L. T. van den Akker, Linda J. Schoonmade, Marry M. van den Heuvel-Eibrink, Martha A. Grootenhuis, Raphaële R. L. van Litsenburg Psycho-Oncology. 2021 Jul;30(7):1009-1028 *Contributed equally

30 Chapter 2 ABSTRACT Objective Steroids play an essential role in treating pediatric acute lymphoblastic leukemia (ALL). The downside is that these drugs can cause severe side effects, such as adverse psychological reactions (APRs) and sleep problems, which can compromise health-related quality of life. This study aimed to systematically review literature to identify risk factors for steroidinduced APRs and sleep problems in children with ALL. Methods A systematic search was performed in six databases. Titles/abstracts were independently screened by two researchers. Data from each included study was extracted based on predefined items. Risk of bias and level of evidence were assessed, using the Quality In Prognosis Studies tool and the Grading of Recommendations Assessment, Development and Evaluation tool, respectively. Results Twenty-four articles were included. APR measurement ranged from validated questionnaires to retrospective record retrieval, sleep measurement included questionnaires or actigraphy. Overall, quality of evidence was very low. Current evidence suggests that type/dose of steroid is not related to APRs, but might be to sleep problems. Younger patients seem at risk for behavior problems and older patients for sleep problems. No studies describing parental stress or medical history were identified. Genetic susceptibility associations remain to be replicated. Conclusions Based on the current evidence, conclusions about risk factors for steroid-induced adverse psychological reactions or sleep problems in children with ALL should be drawn cautiously, since quality of evidence is low and methods of measurement are largely heterogeneous. A standardized registration of steroid-induced APRs/sleep problems and risk factors is warranted for further studies in children with ALL.

31 Risk factors: a systematic review 2 INTRODUCTION Glucocorticoids, such as prednisone and dexamethasone, were among the first drug classes successfully used in the treatment of childhood acute lymphoblastic leukemia (ALL) and are still regarded as cornerstones of ALL therapy.1 These drugs have contributed substantially to the current 5-year overall survival of more than 90% in developed countries.2 However, glucocorticoids can also cause severe side effects, such as osteonecrosis, hyperlipidemia, hyperglycemia, altered body composition, and thromboembolisms.3 Besides these physical toxicities, steroid treatment can cause severe adverse psychological reactions (APRs). These include mood swings, behavioral changes, but also anxiety, psychosis and depression.4,5 Steroid related APRs in ALL are experienced as the most detrimental contributor to impaired health-related quality of life (HRQoL) by both patients and parents.6 Reports on estimated frequencies of steroid-induced APRs in children range from 5% to 75%.5,7-10 Closely related to APRs and also common in children with ALL, are sleep problems, with an estimated prevalence of 19% to 87%.9,11 Steroid-induced APRs and sleep problems are often studied and reported as separate phenomena in pediatric ALL literature.9,12,13 However, sleep problems interrelate with APRs by being both a symptom of certain APRs, such as depression or psychosis, as well as a risk factor to develop APRs.14 Additionally, during ALL steroid-treatment sleep problems significantly impact the quality of life of children.15 An important step to handle both APRs and sleep problems is to identify potential risk factors, making early recognition of susceptible patients possible. This may allow implementation of early intervention strategies to potentially prevent or overcome APRs and sleep problems and their related HRQoL impairments. This was recently acknowledged by the International Psycho-Oncology Society Pediatrics Special Interest Group, which published a call for awareness of sleep problems in pediatric oncology. One of their recommendations was to identify risk factors.16 In adults (both with and without cancer diagnosis), a higher steroid dose as well as past psychiatric history increases the risk of APRs.17,18 In children, only the use of dexamethasone (in comparison to prednisone) appears to influence the occurrence of steroid-induced APRs.19 Known risk factors for sleep problems in the general population are female sex, familial (genetic) predisposition, history of sleep problems, personality type or having a parent with depression.20-23 Although some possible risk factors for APRs and sleep problems have been described, findings in pediatric oncology are often conflicting or not specific for steroid-induced problems.5,24,25

32 Chapter 2 Therefore, this systematic review aimed to summarize all available literature to identify potential risk factors for steroid treatment-induced APRs and sleep problems in children with ALL. APRs and sleep problems are closely linked and may influence each other, however since both phenomena are often described separately, we reviewed them individually as well. To address our aim, we formulated several research questions (with reference to patient population, interventions, comparisons, and outcomes [PICO]). Our patient population encompassed children (0 till 18 years old) with ALL receiving steroid treatment. The outcome parameters were either APRs or sleep problems (or both). Based on previous literature, we hypothesized that the following risk factors might contribute to APRs and/ or sleep problems (interventions and comparisons): sociodemographic factors (age and sex),5,24 treatment factors (type and dose of steroid),5,10,19,24,26 parental factors (coping strategies, stress),27-29 (medical) history,20,30 and genetic predisposition.24,31 However, we did not limit our search on these risk factors. See Supplemental Table 1 for an overview of the PICOs.

33 Risk factors: a systematic review 2 METHODS The protocol of this study was based on the PRISMA statement.32 The study was registered in PROSPERO international prospective register of systematic reviews during the data extraction phase (registration number CRD42020167173). Search strategy and information sources A comprehensive search was performed using the bibliographic databases PubMed,, Scopus, the Cochrane Library, Cinahl (via Ebsco) and PsycINFO (via Ebsco) from inception to 15 August 2019 in collaboration with a medical librarian (Linda J. Schoonmade, Annelienke M. van Hulst and Shosha H.M. Peersmann). Search terms included controlled terms (MeSH in PubMed, Emtree in Embase, Thesaurus terms in Cinahl and PsycINFO) as well as free text terms. The following search terms were used (including synonyms and closely related words) as index terms or free-text words: “ALL” and “children” and ‘steroids” and “adverse effects” or “APR” or “sleep problems.” The search was performed without date or language restrictions. Duplicate articles were excluded. The full search strategy for all databases can be found in Appendix 1. In addition, reference lists of all included studies and relevant reviews were manually searched (cross-reference check) for potential additional studies by two authors (Annelienke M. van Hulst and Shosha H.M. Peersmann). Eligibility criteria and study selection All studies were independently screened by two researchers (Annelienke M. van Hulst and Shosha H.M. Peersmann). First, studies were screened on title and abstract using reference program Rayyan.33 Studies that met the following predefined inclusion criteria were included: (a) study population of children aged 0–18 years old, (b) diagnosed with ALL, (c) receiving steroids (e.g., dexamethasone, prednisone) as part of their leukemia treatment, (d) including an APR or sleep outcome. All types of outcome measurements (questionnaires, observational, chart review, and actigraphy) were deemed eligible. Studies were excluded if they only entailed adults or animals, were nonpeer reviewed (congress abstract/poster), only reported neurocognitive measures or nonacute behavioral or sleep outcomes (late effects). Second, full-texts were screened and included if any of the risk factors of behavior and sleep mentioned above were evaluated. As stated before, risk factors that were not predefined could also be included. Studies were excluded if no original data was reported (reviews), it entailed a duplicate, a case report (series) or if full-text was unavailable. Case reports and relevant reviews were set aside to check references. In addition, articles that reported on outcomes of ALL trials were kept apart, as these articles were not designed to meet

34 Chapter 2 aforementioned inclusion criteria, but were regarded as potentially discussing APRs or sleep problems as part of toxicity registration during trials. Therefore, the full texts of these articles were reviewed as well. Data extraction Data from each study were extracted independently by two authors (Annelienke M. van Hulst and Shosha H.M. Peersmann) based on predefined items: study design, number of participants, mean age, type and dose of steroids, type of APR/sleep outcome, method of measuring APR/sleep outcome, risk factors, method of measuring risk factors and results (often descriptive/percentages). Disagreements were resolved by consensus (Annelienke M. van Hulst and Shosha H.M. Peersmann). If necessary, a third reviewer was consulted (Raphaële R. L. van Litsenburg). Assessment of risk of bias of individual studies To assess risk of bias, the Quality In Prognosis Studies (QUIPS) tool was used. The QUIPS systematically appraises risk of bias in individual studies of prognostic (risk) factors.34 The Cochrane Prognosis Methods Group recommends the use of this instrument.35 The QUIPS ascertains high, moderate or low risk of bias on six domains: (1) study participation, (2) study attrition, (3) prognostic factor measurement, (4) outcome measurement, (5) study confounding, and (6) statistical analysis and reporting. Each study was independently rated using the QUIPS tool by Annelienke M. van Hulst and Shosha H.M. Peersmann after which the scores were discussed to resolve any disagreements. A third reviewer was available when necessary (Raphaële R. L. van Litsenburg). In line with the recommendations of Hayden and colleagues (2013), we assessed each domain and did not rate a summated risk of bias score for individual studies based on the six domains.34 See Supplemental Table 2 for definitions and application of the QUIPS domains. To summarize the quality of individual study results, we took into account: the number of QUIPS domains scoring high on risk of bias, the sample size of APRs/sleep outcomes and whether a study was a priori designed to study risk factors of steroid-induced APRs or sleep problems. We considered a study of lower quality when it entailed more high risk of bias domains, was not a priori designed and had a small sample size. A color-coding was used to indicate our considerations: red (lower quality), orange (medium quality), and green (higher quality). Assessment of grading evidence across studies and synthesis of results To systematically evaluate the quality of summated evidence for each study question and to identify the level of evidence for each risk factor of either APR or sleep problems, we used the Grading of Recommendations Assessment, Development and Evaluation

35 Risk factors: a systematic review 2 (GRADE) tool.36 This tool is recommended by the Cochrane Prognosis Methods Group.35 The GRADE includes a synthesis of results (combined number of participants, studies, cohort phase study and either a positive, negative or no effect) and scores each factor of the GRADE framework: (a) study limitations, (b) inconsistency, (c) indirectness, (d) imprecision, (e) publication bias, (f) effect sizes, and (g) dose effect. See Supplemental Table 3 for definitions and application of the GRADE domains. All evidence for each PICO (Supplemental Table 1) was independently assessed by Annelienke M. van Hulst and Shosha H.M. Peersmann. Besides the predefined PICOs, we also identified new risk factors from literature. Taking into account the combined GRADE synthesis and ratings, the overall level and quality of evidence was determined: + very low, ++ low, +++ moderate, or ++++ high quality. Individual synthesis and ratings (Annelienke M. van Hulst and Shosha H.M. Peersmann) were discussed until consensus was reached. If necessary, a third reviewer was consulted (Raphaële R. L. van Litsenburg). The results of the grading provide an overview of the results per risk factor and the (gaps of) evidence for each risk factor of developing either APRs or sleep problems.

36 Chapter 2 RESULTS Our search yielded 8626 unique records after duplicate removal (Supplemental Figure 1: PRISMA Flow diagram). Hundred and ninety full texts were screened of which 23 articles were included. Furthermore, 245 ALL trial papers were screened of which one article was eligible, resulting in a total of 24 articles included in this review. Nineteen studies reported on risk factor(s) for steroid-induced APRs, whereas seven studies reported on risk factor(s) for steroid-induced sleep problems. Two studies described risk factors for both APRs and sleep problems. See Tables 1 and 2 for all study characteristics, results and quality of each individual study based on risk of bias. Supplemental Table 4 depicts the risk of bias domain scoring within the separate studies. The summated evidence for each identified risk factor of either APRs or sleep problems and the evaluation of evidence using GRADE is shown in Tables 3 and 4 respectively. Adverse psychological reactions Different APRs were described in the included articles: neuropsychiatric signs, toxicities, or adverse events, personality or behavioral change, steroid psychosis, child difficulties, psychiatric disorders and (neuro)behavioral problems. The measurement of these APRs ranged from using validated questionnaires to retrospective collection from patient files. Eleven studies collected any information of APRs without the use of a validated questionnaire.37-47 The other eight studies used five different parent reported questionnaires: Conners rating scale,48,49 Child Difficulties questionnaire,50,51 Child Behavior Checklist,4,25,49,52 Children’s Depression Inventory,49 and the Strength and Difficulties Questionnaire.9,53 Assessment of the different risk factors depended on the nature of the risk factor. For example, sociodemographic factors were retrieved from patient records, whereas treatment factors usually were per protocol. APRs were measured during (remission-)induction4,37-40,43-47 or maintenance phase9,25,37,41,46,48,49,51-53 (unclear in one study42). Overall, the quality of evidence regarding risk factors for APRs was very low (Table 3). Sociodemographic factors (age and sex) Nine studies evaluated age as a risk factor for steroid-induced APRs. Three studies found younger age (0–6 years old) to be a risk factor for behavioral problems of which two were of higher quality.25,41,52 One study of lower quality comparing patients aged 10–15 years with 16–24 years old described an increased frequency of steroid-induced psychosis in the older age group.42 Five studies of lower quality found no significant impact of age on the development of steroid-induced behavior problems or psychosis.9,40,46,48,49 Two studies used age as interval variable,9,49 but most studies used age group categories with variable