Towards Beating Dexamethasone-Induced Side Effects in Children with Acute Lymphoblastic Leukemia

Glucocorticoids, such as dexamethasone and prednisone, play a crucial role in the treatment of childhood acute lymphoblastic leukemia (ALL). Dexamethasone is currently the preferred glucocorticoid and is administered during maintenance therapy for five days every 3-4 weeks over 1.5 years of treatment. However, dexamethasone is associated with various undesirable side effects, including neurobehavioral and sleep problems, increased hunger, dyslipidemia, and adiposity. The prevalence of these side effects varies among patients, and there are no clear risk factors identified.

The first aim of this thesis was to enhance our understanding of the prevalence and determinants of dexamethasone-induced side effects in children with ALL. Our systematic literature review suggested that the type or dose of steroid wasn't related to neurobehavioral problems but might be to sleep problems. Younger patients appeared at risk for behavioral problems, while older patients were at risk for sleep problems. Parental stress and medical history had not been well-studied, and genetic susceptibility associations required further validation.
Our prospective cohort study involving 105 children with ALL found that parents frequently reported clinically relevant neurobehavioral (67%) and sleep problems (59%). Surprisingly, parenting stress, and not dexamethasone pharmacokinetics, genetics, demographics, or disease and treatment factors, emerged as a significant determinant for parent-reported dexamethasone-induced neurobehavioral and sleep problems. This highlights the potential for addressing parenting stress to reduce these issues.

Our study also demonstrated that just five days of dexamethasone led to a notable increase in leptin (a hormone regulating satiety), hunger scores, and fat mass. However, there were no correlations between these measurements, suggesting the possibility of dexamethasone-induced acute leptin resistance, which is of concern given the increased risk of metabolic adverse events in children with ALL.

Despite the well-known side effects of dexamethasone, there is currently no pharmacological treatment to mitigate them. Previous research showed that hydrocortisone may be beneficial in reducing neurobehavioral and sleep problems in those patients who suffer most. The second aim of this thesis was to validate the finding that hydrocortisone addition leads to a reduction in clinically relevant dexamethasone-induced neurobehavioral and sleep problems. However, our study found that there was no significant difference between hydrocortisone and placebo in reducing these problems. Instead, it suggested that a placebo effect influenced both patients and families, providing some relief from dexamethasone-induced neurobehavioral problems.

Lastly, this thesis explored the cytotoxic effects of hydrocortisone and the role of mineralocorticoid receptors in steroid-induced cytotoxicity. Preclinical research revealed that hydrocortisone can induce the expression of steroid-regulated genes through both glucocorticoid and mineralocorticoid receptors and effectively induce cell death in leukemic cell lines. Patient samples indicated a less pronounced role of the mineralocorticoid receptor in steroid-induced cytotoxicity.

In conclusion, this research offers important insights into the prevalence and determinants of dexamethasone-induced side effects in childhood ALL. While no pharmacological treatment currently exists to eliminate these side effects, our findings suggest potential approaches for alleviating the burden, including addressing parental stress. Additionally, the placebo effect may provide some relief to patients and families facing these challenges during the course of ALL treatment.