Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

2007 ◽  
Vol 50 (3) ◽  
pp. 537-541 ◽  
Author(s):  
Silvia Einaudi ◽  
Nicoletta Bertorello ◽  
Nicoletta Masera ◽  
Loredana Farinasso ◽  
Elena Barisone ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Steroid Therapy ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
High Dose ◽  
High Dose Steroid ◽  
Adrenal Axis

scholarly journals Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (9) ◽  
pp. 949-959 ◽  
Author(s):  
Deepa Bhojwani ◽  
Noah D. Sabin ◽  
Deqing Pei ◽  
Jun J. Yang ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Brain Magnetic Resonance Imaging ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Asymptomatic Patients ◽  
A Genome ◽  
Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice.

1995 ◽  
Vol 13 (10) ◽  
pp. 2490-2496 ◽  
Author(s):  
D P Waber ◽  
N J Tarbell ◽  
D Fairclough ◽  
K Atmore ◽  
R Castro ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Verbal Memory ◽  
Lymphoblastic Leukemia ◽  
Cognitive Outcome ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Consistent Finding ◽  
Dose Methotrexate ◽  
Cognitive Sequelae

PURPOSE We evaluated cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL). CNS therapy consisted of cranial irradiation (CRT) or no radiation. Children were also randomized to single intravenous high-dose methotrexate (HD-MTX) or conventional-dose methotrexate (CD-MTX) during induction, and all patients received intrathecal (IT) and systemic continuation chemotherapy. PATIENTS AND METHODS Sixty-six patients treated for ALL on Dana-Farber Cancer Institute protocol 87-01 were evaluated by standardized cognitive and achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received no CRT or 18 Gy CRT, respectively. All patients were randomized to receive MTX during remission induction, either as CD-MTX (40 mg/m2) or HD-MTX (4 g/m2) with leucovorin rescue. RESULTS There was no difference in cognitive outcomes between radiated and unirradiated patients (P > .4). However, the HD-MTX/CRT combination was associated with decreased intelligence quotient (IQ estimate, 9.3 points) for girls only (P < .08). A specific deficit in verbal coding and memory was documented for all patients (P < .0001). CONCLUSION We conclude the following: (1) 18 Gy CRT per se was not an independent toxic agent for cognitive outcome; (2) HD-MTX during induction was associated with IQ decline in girls, but only when it was followed by CRT; and (3) impairment of verbal memory and coding was a consistent finding that was independent of CRT, which implicates some component of chemotherapy, possibly prednisone, as a CNS toxin.

HEMOSTATIC SIDE EFFECTS OF HIGH-DOSE METHOTREXATE IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA

2004 ◽  
Vol 21 (1) ◽  
pp. 77-83 ◽  
Author(s):  
Tunc Fisgin ◽  
Nese Yarali ◽  
Abdurrahman Kara ◽  
Ceyhun Bozkurt ◽  
Dilek Birgen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia.

1993 ◽  
Vol 11 (5) ◽  
pp. 827-833 ◽  
Author(s):  
C Wolfrom ◽  
R Hartmann ◽  
R Fengler ◽  
S Brühmüller ◽  
A Ingwersen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Serum Levels ◽  
Multicenter Trial ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
High Dose ◽  
Median Serum ◽  
Steady State Levels ◽  
Intermediate Dose

PURPOSE Pharmacokinetics, toxicity, and therapeutic efficacy of two different methotrexate (MTX) infusions for remission induction of relapsed childhood acute lymphoblastic leukemia (ALL) were investigated in a randomized multicenter trial. PATIENTS AND METHODS Sixty patients with early bone marrow relapse received a polychemotherapy induction protocol starting with either 12 g/m2 MTX as a 4-hour infusion (high-dose [HDM]) or 1 g/m2 as a 36-hour infusion (intermediate-dose [IDM]). In HDM, leucovorin (LCV) was administered orally (12 times, 15 mg/m2 every 6 hours), beginning at hour 24. In IDM, only two doses were administered at hours 48 and 54. RESULTS Median serum MTX concentrations during infusion were 716 mumol/L in HDM and 7.2 mumol/L in IDM. In HDM, MTX serum levels at hour 24 (median, 2.8 mumol/L) were significantly less than steady-state levels of IDM. Concentrations greater than 1 mumol/L were maintained for 36 hours with HDM and 45 hours with IDM. General tolerance to treatment was better in the HDM group. Mucosal lesions occurred significantly more often and were more severe after IDM treatment. A median treatment delay of 3 days was required in the IDM group but not in the HDM group. At day 15, complete remission (CR) was documented in 45% of IDM- and 48% of HDM-treated patients. Persistent blasts (> 5%) appeared more frequently in HDM than in IDM (35% v 19% of patients; P = NS). After completion of induction therapy, 28 of 30 patients in each group achieved CR. CONCLUSION Both regimens produced the same remission rates. The tendency to better antileukemic activity of IDM was accompanied by more severe side effects as a consequence of long-lasting cytotoxic MTX levels. Hence, long-term infusion of IDM followed by low-dose LCV is an effective treatment for recurrent ALL.

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