title: Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421.
abstract: Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: David
authors.initials: D
authors.lastname: Becton
authors.forename: Gary V
authors.initials: GV
authors.lastname: Dahl
authors.forename: Yaddanapudi
authors.initials: Y
authors.lastname: Ravindranath
authors.forename: Myron N
authors.initials: MN
authors.lastname: Chang
authors.forename: Fred G
authors.initials: FG
authors.lastname: Behm
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: David R
authors.initials: DR
authors.lastname: Head
authors.forename: Kimo C
authors.initials: KC
authors.lastname: Stine
authors.forename: Norman J
authors.initials: NJ
authors.lastname: Lacayo
authors.forename: Branimir Ivan
authors.initials: BI
authors.lastname: Sikic
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: Howard
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D007958:Leukocyte Count; D008297:Male; D008936:Mitolactol / Q000008:administration & dosage; D012074:Remission Induction; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D013629:Tamoxifen; D004317:Doxorubicin; D016572:Cyclosporine; D008936:Mitolactol