The glucocorticoid receptor gene polymorphism N363S predisposes to more severe toxic side effects during pediatric acute lymphoblastic leukemia (ALL) therapy
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The survival rates in childhood acute lymphoid leukemia (ALL) have improved dramatically; however, patients still suffer from a variety of drug-related toxicities. Individualized therapy regimens promise the least toxic therapy regimen with the best hematologic outcome. Our aim was to investigate whether increased individual glucocorticoid sensitivity due to the N363S polymorphism of the glucocorticoid receptor increased susceptibility to steroid-related toxicities during ALL therapy. A total of 346 pediatric ALL patients were involved in the present study. N363S carrier status was investigated by allele-specific PCR. Clinical and laboratory signs of glucocorticoid-related toxicities, Day 8 prednisone response, and 5-year event-free survival were analyzed and compared retrospectively. Thirty-two of the 346 patients were heterozygous carriers (9.2 %). Hepatotoxicity (31.3 vs. 11.2 %, p = 0.004, carriers and non-carriers, respectively) and glucose metabolism abnormalities (18.8 vs. 3.8 %, p = 0.001, carriers and non-carriers, respectively) were significantly more frequent among carriers. There was no difference in the incidence of hypertension and encephalopathy/psychosis among carriers and non-carriers. Carriers were also more prone to have a combination of toxicities. All 363S carriers were good prednisone responders (100 %) and had significantly better 5-year event-free survival rates (93.1 vs. 71.86 %, p = 0.012), whereas among non-carriers there were more poor prednisone responders (8.28 %) and worse 5-year event-free survival rates. Patients with the N363S polymorphism in the glucocorticoid receptor are more prone to steroid-related toxicity during ALL therapy and should be monitored more closely. Patients with N363S polymorphism of the glucocorticoid receptor may be appropriate candidates for inclusion in the design of individualized therapies.
KeywordsAcute lymphoid leukemia Glucocorticoid receptor Single nucleotide polymorphism Steroid-related toxicities Individualized therapy
We wish to express our sincere gratitude to all nurses and doctors who took part in this study, especially to the following hematological department leaders who provided us the opportunity to get all the important clinical and laboratory data and blood samples for this study: Katalin Bartyik, Head of the Department of Pediatric Oncology, University of Szeged Medical Center, Szeged, Hungary; Csongor Kiss, M.D., Ph.D., D.Sc.: Head of the Department of Pediatric Oncology, University of Debrecen Medical Center, Debrecen, Hungary; Kálmán Nagy MD,PhD,Csc: Head of the Department of Hematology, Child Welfare Center, Borsod County Teaching Hospital, Miskolc, Hungary; Gábor Ottóffy MD: Head of the Department of Pediatric Oncology, University of Pécs Medical Center, Pécs, Hungary.
Conflict of interest
All authors declare no real or apparent conflicts of interest. None of the authors have competing interest.
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