title: Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia.
abstract: Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia.
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Janke
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Monique A
authors.initials: MA
authors.lastname: Payton
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Paugh
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Seth E
authors.initials: SE
authors.lastname: Karol
authors.affiliation: Harding University College of Pharmacy, Searcy, Arkansas, United States of America.
authors.forename: Landry
authors.initials: L
authors.lastname: Kamdem Kamdem
authors.affiliation: Biostatistics Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Puma Biotechnology Inc., Los Angeles, California, United States of America.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003345:Corticosterone / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010020:Osteonecrosis / Q000517:prevention & control; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D003907:Dexamethasone; D016044:Fusion Proteins, bcr-abl; D003345:Corticosterone