Evaluation of the hypothalamic-pituitary-adrenal axis in children with leukemia before and after 6 weeks of high-dose glucocorticoid therapy. Impaired adrenal function after glucocorticoid therapy in children with acute lymphoblastic leukemia. Clinical impact of corticosteroid-induced adrenal suppression during treatment for acute lymphoblastic leukemia in children: a prospective observational study using the low-dose adrenocorticotropin test. Early adrenocortical recovery after glucocorticoid therapy in children with leukemia. Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia. Time course of recovery of adrenal function in children treated for leukemia. Suppression of adrenal function in children with acute lymphoblastic leukemia following induction therapy with corticosteroid and other cytotoxic agents.
Among the adverse effects arising from chronic high-dose glucocorticoid treatment, adrenal insufficiency secondary to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a cause for concern. Glucocorticoid-induced adrenal suppression is related to the duration of therapy, type of steroid used and dosage, and schedule of glucocorticoid administration. To evaluate the suppression and recovery time of the HPA axis in children with acute leukemia, we performed the ovine CRH (oCRH) stimulation test in 15 patients, who were given high doses of dexamethasone as part of their induction chemotherapy for 42 days. The oCRH tests were performed before, and 7 and 14 days after, discontinuation of the glucocorticoid. The ACTH levels were not significantly different among the 3 tests. The cortisol levels, however, were significantly (albeit mildly) lower, both basally and after oCRH, 1 and 2 weeks post treatment than before therapy. Six patients had cortisol values that remained suppressed 2 weeks after discontinuation of therapy. One of these patients had manifestations of mild adrenal insufficiency, 6-8 days after discontinuation of therapy, but required no glucocorticoid coverage. We conclude that up to 2 weeks after discontinuation of 6 weeks of high-dose dexamethasone administration, the HPA axis of patients with acute leukemia is mildly suppressed but infrequently associated with clinical manifestations of adrenal insufficiency. This may indicate that major stress, when concurrent with glucocorticoid treatment, may prevent clinically significant adrenal suppression. Glucocorticoids are commonly used in the treatment of childhood acute lymphoblastic leukemia (ALL). The purpose of this study was to assess the incidence of adrenal insufficiency and the time for children with ALL to recover after treatment with the glucorticoids prednisolone or dexamethasone.
                Seventeen children, 2-15 years, with ALL were studied after receiving prednisolone (60 mg/m(2)/day, n = 10) for 5 weeks during remission induction therapy or dexamethasone (10 mg/m(2)/day, n = 7) for 3 weeks during reinduction therapy. Both drugs were tapered over 9 days. The adrenal function was assessed by an ACTH stimulation test within 2 weeks after discontinuing glucocorticoid therapy. In case of adrenal insufficiency, the ACTH test was repeated at 3-5 weeks interval, and patients were put on hydrocortisone substitution therapy.
                Three out of ten patients had a normal adrenal function within the first 2 weeks after prednisolone therapy. Another three patients recovered within 7 weeks, whereas the remaining four patients still showed adrenal insufficiency at the end of follow-up after 2.5-4 months. For dexamethasone, two out of seven patients showed a normal adrenal function within the first 2 weeks. Of the remaining patients, two recovered within 7 weeks, whereas three patients still had a demonstrated adrenal insufficiency at the end of follow-up after 4-8 months.
                Adrenal insufficiency occurs and may persist for several months in children with ALL after treatment with high doses of prednisolone or dexamethasone.
                Copyright 2003 Wiley-Liss, Inc. To investigate how frequently adrenal function fails to recover after corticosteroid therapy in children with acute lymphoblastic leukemia and to explore the clinical impact of slow adrenal recovery without steroid substitution.
                Low-dose (1 microg) adrenocorticotropic hormone tests were performed before and after steroid courses and during infectious episodes in 24 children. Test results were not available during the study.
                All 13 patients tested before treatment had normal adrenal responses. Adrenal suppression was found in 8 (47%) of 17 patients 5 days after discontinuation of a 5-week induction course of prednisolone and in 1 (20%) of 5 patients 7 days after a 3-week intensification course of dexamethasone, both courses being tapered over 9 days, as well as in all 13 patients tested 2 days after a 1-week prednisolone course. Clinically significant manifestations of adrenal suppression were noted in 3 (12%) patients. Of 204 scheduled tests, 131 were performed.
                High-dose glucocorticoid therapy may cause adrenal suppression lasting more than 1 week in children with acute lymphoblastic leukemia, even after tapering the dose. We suggest steroid replacement during stress episodes within 1 to 2 weeks after discontinuation and thereafter testing adrenal function selectively in accordance with symptoms. The duration of glucocorticoid-induced inhibition that occurs in the hypothalamic-pituitary-adrenal (HPA) axis after discontinuation of treatment is controversial. The main objective of this prospective study was to evaluate the inhibition of the HPA axis by dexamethasone in children and adolescents with acute lymphoid leukemia. Thirty-five patients (median age of 6.9 yr) were evaluated. A stimulus test with ovine CRH (1 microg/kg) was performed before the introduction of dexamethasone (6 mg/m2.d for 28 d), in the 8th and 28th days of glucocorticoid therapy, and 48 h and 1 month after discontinuation of glucocorticoid therapy. Suppression of the basal secretion as well as the maximum concentration of ACTH occurred during glucocorticoid therapy (P < 0.01). The pituitary function before the introduction of dexamethasone was similar to the one seen 48 h and 1 month after withdrawing it. Suppression of the adrenal function was detected during glucocorticoid therapy, which persisted for 48 h after the steroid was removed from treatment (P < 0.01). One month after ceasing the administration of the glucocorticoid, the adrenal function was similar to that before glucocorticoid therapy. According to these results, a clinical and laboratory follow-up of the HPA axis in the month after the cessation of dexamethasone therapy is suggested to determine glucocorticoid replacement. A 4-week course of high-dose glucocorticoids may cause prolonged adrenal suppression even after a 9-day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high-dose prednisone (PDN) or dexamethasone (DXM).
                Sixty-four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD-ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1-2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period.
                All patients had normal basal cortisol values at diagnosis. Twenty-four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD-ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7-14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression.
                High-dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated.
                (c) 2007 Wiley-Liss, Inc. Many protocols for treating children with early B-cell lineage acute lymphoblastic leukemia use 28 consecutive days of high-dose glucocorticoids during induction therapy. We prospectively studied the effects of this therapy on adrenal function.
                Ten children with early B-cell lineage acute lymphoblastic leukemia were evaluated by cosyntropin (corticotropin (1-24)) stimulation testing before initiation of dexamethasone therapy and every 4 weeks thereafter until adrenal function returned to normal.
                All 10 patients had normal adrenal function before dexamethasone treatment and insufficient adrenal responses 24 hours after completing therapy. Each child felt ill for 2 to 4 weeks after completing therapy. Although 7 patients recovered normal adrenal function after 4 weeks, 3 patients did not have normal adrenal function until 8 weeks after discontinuing therapy. Statistically significant differences in both basal and corticotropin-stimulated cortisol levels were noted when comparing tests performed at baseline, 24 hours after completing therapy, and 4 weeks after completing therapy.
                High-dose dexamethasone therapy, a standard treatment for early B-cell acute lymphoblastic leukemia, can cause adrenal insufficiency lasting more than 4 weeks after cessation of treatment. This problem might be avoided by tapering doses of glucocorticoids and providing supplemental glucocorticoids during periods of increased stress. To evaluate adrenal function in children with acute lymphoblastic leukemia (ALL) after induction therapy with corticosteroid and other cytotoxic agents. Study design Children with ALL (N=24) were treated with prednisolone (40 mg/m(2) per day) for 28 days during the induction phase followed by 1 week of oral dexamethasone every 4 weeks. A low-dose (1 microg) adrenocorticotropin (ACTH) test was performed 2 weeks after discontinuation of prednisolone; it was repeated 2 weeks later and then every 4 weeks in patients with adrenal suppression until normal response was achieved.
                Adrenal suppression was found in 46% of patients at 2 weeks after discontinuation of prednisolone; it persisted in 38%, 29%, and 13% of patients through 4 weeks, 8 weeks, and 20 weeks, respectively. Adrenal suppression appeared to last significantly longer in children aged >or=5 years than in children aged <5 years. Four children developed febrile neutropenia; all belonged to the adrenal suppressed group and were unable to mount an adequate adrenal response to the stress.
                About 50% of children with ALL developed adrenal suppression 2 weeks after a 4-week induction therapy with prednisolone. The suppression could persist through 20 weeks and may hinder an adequate adrenal response during acute febrile illness.
Based on the available evidence, we conclude that adrenal insufficiency commonly occurs in the first days after cessation of glucocorticoid therapy for childhood ALL, but the exact duration is unclear. Since no data on the level of the hypothalamus and the pituitary were available we cannot make any conclusions regarding those outcomes. Clinicians should consider prescribing glucocorticoid replacement therapy during periods of serious stress in the first weeks after cessation of glucocorticoid therapy for childhood ALL, to reduce the risk of life-threatening complications. However, more high-quality research is needed for evidence-based guidelines for glucocorticoid replacement therapy.
Special attention should be paid to patients receiving fluconazole therapy, and perhaps similar antifungal drugs, as this may prolong the duration of adrenal insufficiency.