Double blind placebo controlled randomized intervention study to validate the beneficial effect of hydrocortisone on dexamethasone-induced neurobehavioral side effects in pediatric acute lymphoblastic leukemia

Dexamethasone, a highly effective drug in treating pediatric acute
lymphoblastic leukemia (ALL), can induce serious neurobehavioral side effects.
These are experienced as extremely detrimental with respect to quality of life
by patients and parents. For a long time, the underlying mechanism of
dexamethasone induced neurobehavioral side effects was poorly understood.
However, recent studies emphasized that cortisol depletion of the
mineralocorticoid receptor (MR) in the brain might play an important role. This
depletion occurs due to the fact that dexamethasone has a low affinity for the
MR and suppresses the endogenous cortisol production. Addition of cortisol
(hydrocortisone) to dexamethasone treatment could overcome this depletion. In
our recent randomized controlled trial, the Dexadagen study, we found that
clinically relevant neurobehavioral and sleeping problems decrease by
hydrocortisone addition during dexamethasone treatment. Validation is required
in a selected larger sample size. The inclusion for this part of our study
closed on 5-8-2020 since enough patients were entered in the study.

There are big differences in the amount of experienced dexamethasone induced
problems. There are possible determinants that could explain these differences.
We will study 3 possible determinants of the inter-patient variability in the
occurrence of dexamethasone induced neurobehavioral problems:
1. Genetic predisposition: throug SNP array polymorphisms of the
mineralocorticoid receptor and glucocorticoïd receptor genes which are
associated with behavioral and sleeping problems will be investigated in a
large sample size (105 children).
2. Dexamethasone kinetics will be studied through peak and trough levels.
3. Environmental and psychosocial factors such as parental stress, family
background, education and support will be investigated through several
questionnaires.

Besides neurobehavioral problems, dexamethasone therapy is known to cause
metabolic side effects. Furthermore, children with ALL experience muscle
wasting during treatment, and it has recently been shown that childhood cancer
survivors have a high risk of frailty. Frailty is a state of reduced
physiologic reserve that is associated with increased susceptibility to chronic
disease and disability and is mostly described in older adults. It is
characterized by a combination of three of the following five measurements of
physical abilities: poor muscle mass, poor muscle strength, fatigue, slow
walking performance and physical inactivity .
So far, frailty has never been examined in childhood cancer patients during
their treatment. In our previous study, we showed that merely 4 days of
dexamethasone treatment can induce metabolic toxicity on three components of
the metabolic syndrome in children with ALL. In our current study, we want to
examine the acute effect of dexamethasone treatment on frailty. Futhermore, we
want to determine the prevalence of vitamin D and B as well as other nutrient
and hormone (e.g. leptin) deficiencies, the effect of dexamethasone on these
deficiencies and the association between nutrient deficiencies and frailty
occurrence.

The primary aim is to validate the finding that addition of physiological doses
of hydrocortisone reduces dexamethasone-induced clinically relevant
neurobehavioral problems. The secondary aims are to study the role of genetic
variation, psychosocial factors, and pharmacokinetics as determinants of
dexamethasone induced neurobehavioral problems and to investigate sleeping
problems, quality of life, frailty and vitamin/nutrient deficiencies after 5
days of dexamethasone treatment with or without hydrocortisone addition.

We will perform a prospective double blind placebo-controlled randomized
cross-over study. Patients with clinically relevant neurobehavioral problems
(defined as an increase of *5 points on the Strengths and Difficulties
Questionnaire (SDQ)) will receive hydrocortisone or placebo during 2
consecutive 5 day courses of dexamethasone and thereafter cross over. We will
investigate clinically relevant sleeping problems (defined as an increase of *7
points on the Sleep Disturbance Scale for Children (SDSC)) and quality of life
(measured with the Pediatric Quality of Life questionnaire (PedsQL)). Frailty
will be evaluated both in the RCT as in the Identification study.
Vitamin/nutrient deficiencies will be studied in all patients. The RCT was
closed on 5-8-2020 since 50 patients were included.

Besides the RCT we want to investigate possible determinants of the
inter-patient variability of dexamethasone induced neurobehavioral side effects
in an identification study:
1. The influence of several polymorphisms using a candidate SNP approach
2. The role of dexamethasone pharmacokinetics
3. The impact of psychosocial and environmental factors

The prevalence of frailty and several vitamin/nutrient/hormone deficiencies
will be studied as well. Frailty is defined as having 3 or more of the
following 5 physical indicators:
1. Sarcopenia, measured with bio-electrical impedance analysis, muscle
ultrasonography and leg circumference.
2. Fatigue, measured with PedsQL fatigue questionnaire
3. Slow walking performance, measured with the 'Timed up and go' test
4. Physical inactivity, measured with an activity questionnaire
5. Poor muslce strength, measured with handheld dynamometer and the 'rise from
the floor' test.

We will also ask 5 sarcopenia screening questions (SARC-F) to assess whether
these questions can predict sarcopenia.

During 2 identical periods of 5 days of dexamethasone treatment, in addition,
patients will receive either a physiological dose of hydrocortisone
(intervention) or placebo. In the consecutive 2 periods of dexamethasone
treatment the intervention or placebo will be reversed.

Extent and burden is low. The intervention drug (hydrocortisone) will be given
in a physiological dose, not in a pharmacological dose, which is the equivalent
of a normal cortisol production of the body. We have ample experience with
hydrocortisone in physiological dose in other patient groups, and no side
effects are expected. Our previous pre-clinical in vitro study in leukemic
blasts showed no adverse effect on the antileukemic effect of adding
hydrocortisone to dexamethasone. Furthermore, the RCT (Dexadays 1 study) did
not show any adverse events or side effects during the intervention. Blood
sampling will be done using the existing vascular access ports, during regular
hospital visits only when blood must be drawn or intravenous medication must be
given, therefore minimizing the risk of infection. Patients have one extra
visit to the hospital. Parents and patients will have to fill in
questionnaires, but this will be reduced to minimum and will all be accessible
through one online portal. Furthermore all questionnaires will be filled in
together with the researcher when possible. The frailty measurements are short
and non-invasive. They will take place when a child has a regular visit at the
hospital. The potential benefit of this study is an improvement in quality of
life for patients with clinically relevant dexamethasone induced
neurobehaviroural side effects.