Adrenal function after induction therapy for acute lymphoblastic leukemia in children short: adrenal function in ALL

Abstract

Prednisolone used in the induction phase of the treatment of acute lymphoblastic leukemia (ALL) may suppress hypothalamic-pituitary-adrenal axis and require hydrocortisone substitution. In this retrospective analysis, we reviewed altogether 371 ACTH stimulation tests of 352 children after a uniform NOPHO (Nordic Society of Pediatric Hematology and Oncology) ALL induction. Both low-and standard-dose ACTH tests were used. Full recovery of adrenal function was defined by both normal basal and stimulated cortisol levels. Sixty-two percent of patients were detected with normal adrenal function in median of 15 days after tapering of prednisolone. Both low basal and stimulated cortisol levels were detected in 13% of patients. The median time to normal adrenal function was 31 days (95% CI 28-34), 24 days (95% CI 18-30), and 12 days (95% CI 10-14) for those with basal cortisol <107, 107-183, and >183 nmol/L at first ACTH testing, respectively. Patients with fluconazole prophylaxis had higher median baseline cortisol levels compared to patients without prophylaxis (207 nmol/L, range 21-839 nmol/L vs. 153 nmol/L, range 22-832 nmol/L, P = 0.003).Conclusion: These data can be used to reduce unnecessary substitution or testing, but also to guarantee hydrocortisone substitution for those at risk. What is Known:•These data can be used to reduce unnecessary hydrocortisone substitution or ACTH testing. •Our data helps to guarantee hydrocortisone substitution for those at risk of adrenal insufficiency. What is New:•Full recovery of adrenal function after ALL induction is detected in 62% of patients already at 15 days after tapering of prednisolone.•Both basal and stimulated cortisol testing are required for detection of full adrenal recovery.•Recovery time of adrenal function is extended over 3-4 weeks after tapering of prednisolone in patients with low basal cortisol levels (<107 nmol/L) at first testing.

Adrenal Suppression in Children During the Treatment for Acute Lymphoblastic Leukemia Beyond Induction

“…Research has shown that children receiving induction therapy for ALL during which high dose GC are used, are at high risk of biochemical AS after the end of induction. [2][3][4] In a Cochrane review, 11 of 10 studies including 298 pediatric patients with ALL, almost all patients were found to have biochemical evidence of AS within days of finishing GC therapy. Most children recovered from adrenal insufficiency within 7 weeks.…”

“…Although most patients in that review had AS immediately after GC exposure, some had prolonged AS. In 2 studies where post-induction hydrocortisone replacement was routine, 2,4 patients seemed to have a more prolonged recovery. Extrapolating from these previous studies, our finding of abnormal, although borderline, LDST may represent resolving AS secondary to elapsed time since last GC exposure.…”

“…1 AS has been well described after induction for acute lymphoblastic leukemia (ALL) where supraphysiologic doses of GC are given for up to 28 consecutive days and then stopped irrespective of whether a tapering schedule was followed or not. [2][3][4] Adrenal crisis secondary to AS has also been reported in infants and children undergoing therapy for ALL when presented with even mild or no stressors. 5,6 However, little is known about the risk of AS outside of the induction phase.…”

“…Symptoms of AS are often nonspecific, but the risk of adrenal crisis and mortality are significantly increased when individuals with AS are faced with an intercurrent illness 1 . AS has been well described after induction for acute lymphoblastic leukemia (ALL) where supraphysiologic doses of GC are given for up to 28 consecutive days and then stopped irrespective of whether a tapering schedule was followed or not 2–4 . Adrenal crisis secondary to AS has also been reported in infants and children undergoing therapy for ALL when presented with even mild or no stressors 5,6 .…”

Case Report: Hypercalcemia as a manifestation of acute adrenal crisis precipitated by fluconazole use, and a review of the literature

“…Concurrent use of fluconazole during dexamethasone therapy was associated with prolonged HPA recovery ( 34 ). This is due to the inhibition of CYP3A4 by fluconazole, which results in decreased metabolism of corticosteroid and increased corticosteroid exposure to the HPA axis ( 35 ). Itraconazole is an even more potent inhibitor of CYP3A4, and secondary adrenal insufficiency was reported to occur in a patient on inhaled fluticasone and itraconazole ( 31 ).…”