Hydrocortisone Helps Reduce Serious Neuropsychologic Adverse Events for Pediatric Acute Lymphocytic Leukemia Patients Receiving Dexamethasone

While dexamethasone is a common component of the treatment of pediatric acute lymphocytic leukemia (ALL), the drug can cause serious neuropsychologic and metabolic adverse events (AEs), potentially affecting patients’ mood, behavior, cognition, and sleep. A study published in the Journal of Clinical Oncology suggests that adding a dose of hydrocortisone to dexamethasone treatment could reduce occurrence of severe AEs.

“Dexamethasone treatment in children with ALL can cause robust acute mood, behavioral, and sleeping problems, and can thereby affect quality of life,” first author Lidewij T. Warris, MD, from the Erasmus MC-Sophia Children’s Hospital in Rotterdam, the Netherlands, told ASH Clinical News.

The relationship between dexamethasone treatment and neuropsychologic AEs is not well understood, but recent data suggest that “these neuropsychologic side effects may be due to the cortisol depletion of the cerebral mineralocorticoid receptors (transcription factors that help regulate mood, behavior, cognition, and sleep) during dexamethasone treatment,” Dr. Warris explained.

The researchers tested whether physiologic doses of hydrocortisone could reduce these AEs, in a multi-center, double-blind, randomized, controlled, cross-over study of 48 patients (age range = 3-16 years) recruited from five Dutch pediatric oncology departments. Patients were excluded if they showed any evidence of pre-existing intellectual disabilities or any condition that could have interfered with the administration and/or absorption of the study medication and/or dexamethasone.

During the maintenance phase, patients received 19 consecutive 21-day treatment cycles that included:

  • 5 consecutive days of dexamethasone, including two 5-day courses of dexamethasone 6 mg/m2/day (3 doses containing 2 mg/m2 each)
  • vincristine administered once on the first day of the cycle
  • 6-mercaptopurine administered once per day
  • methotrexate administered once per week

Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m2/day) during both dexamethasone courses. In the cross-over phase, patients who were randomized to receive hydrocortisone in the first course received placebo in the second course and vice versa.

The study’s primary endpoint was reduction of psychosocial problems during dexamethasone treatment, assessed by results of the parent-reported Strengths and Difficulties Questionnaire in Dutch (SDQ). Secondary endpoints included changes in sleep-related difficulties, eating behavior, physical activity, cognitive functions, and metabolic parameters; these were measured by other questionnaires and neuropsychologic tests.

In each treatment course, parents assessed mood, behavior, cognition, and sleep on the morning of the first day of treatment (before the start of dexamethasone treatment) and the morning of the fifth day of treatment (after a full 4 days of dexamethasone treatment).

Forty-six parents (41 mothers and 5 fathers) completed SDQ responses and all indicated that, after four days of dexamethasone treatment, patient problems on all SDQ subscales were significantly increased. In 65 percent of patients (n=30), dexamethasone led to an increase in psychosocial problems (defined as a ≥1-point change in the SDQ “total difficulties” score during the placebo course). One-third of patients did not experience any increase in SDQ total difficulties, and median SDQ total difficulties score for the entire study group on day 5 of placebo was within the normal range.

The addition of hydrocortisone did not affect the total difficulties score for the entire group compared with placebo on scores of:

  • total difficulties (median difference = −0.8; p=0.33)
  • emotional symptoms (median difference = −0.6; p=0.08)
  • conduct problems (median difference = 0; p=1.00)

However, in the 16 patients who experienced severe dexamethasone-associated AEs, the SDQ total difficulties score was increased by ≥5 points. “In these 16 children, hydrocortisone had a clear effect on the total difficulties score compared with placebo (median difference = 25.0; interquartile range [IQR] = 27.8-23.0),” the authors wrote. “In five (31%) of 16 patients, total difficulties score decreased from a high score in the placebo course to a score in the normal range with the addition of hydrocortisone.”

Dr. Warris and authors also observed an effect of hydrocortisone versus placebo on scores for:

  • emotional symptoms (median difference = 21.5; IQR=24.0-21.0)
  • conduct problems (median difference = 21.0; IQR=22.0-0.0)
  • impact of stress (median difference = 21.0; IQR=22.0-0.0)

In the nine patients (19%) who experienced clinically relevant dexamethasone-induced sleeping problems (defined as a change of ≥7 in The Sleep Disturbance Scale for Children [SDSC] total score during the placebo course), hydrocortisone reduced total sleeping problems (median difference in SDSC total scores = −11; IQR=−16 to 0) and disorders of initiating and maintaining sleep (median difference = −3; IQR = −7 to −0.5).

Neuropsychologic test results revealed that dexamethasone alone had no effect on attention, visual-spatial functions, memory, or processing speed, though the addition of hydrocortisone significantly improved long-term visual memory (p=0.01).

Hydrocortisone had no effect on metabolic parameters (including physical activity, eating behavior, weight, height, waist-hip ratio, and blood pressure), leading the authors to believe that metabolic AEs are not mediated by cortisol depletion of the cerebral mineralocorticoid receptors in the same way that neuropsychologic AEs are.

“Physiologic doses of hydrocortisone are relatively inexpensive, provide a naturally occurring hormone, and have no apparent negative effects,” the authors wrote. “This novel, yet simple, intervention has the potential to significantly reduce neuropsychologic AEs in patients who receive high-dose dexamethasone treatment.”

The study is limited by its small patient population, and the authors noted that regression to the mean could have influenced subgroup selection. “Our results should be confirmed, preferably, in a validation study in selected patients with symptoms only,” they concluded, “however, the substantial effect size of the intervention indicates a benefit of hydrocortisone in patients with psychosocial problems and sleeping problems.”


Reference

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. 2016 May 9. [Epub ahead of print]

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