title: Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia.
abstract: Activating mutations of receptor tyrosine kinases (RTKs) and their downstream affectors are common in acute myeloid leukemia (AML). We performed mutational analysis of FLT3, c-kit, c-fms, vascular endothelial growth factor (VEGF) receptors (Flt-1, KDR [kinase domain receptor]), and ras genes in a group of 91 pediatric patients with AML treated on Children's Cancer Group clinical trial CCG-2891. Forty-six percent of patients had activating mutations of FLT3 (24.5%), c-kit (3%), or ras (21%) genes. Mutation-positive patients had a higher median diagnostic white blood cell (WBC) count (71.5 vs 19.6 x 10(9)/L; P =.005) and lower complete remission rate (55% versus 76%; P =.046) than mutation-negative patients. The Kaplan-Meier estimate of overall survival (OS) for patients with and without an activating mutation was 34% versus 57%, respectively (P =.035). However, within this group, patients with FLT3/ALM (activation loop mutation) had good outcomes (OS, 86%). Exclusion of the FLT3/ALM from analysis decreased the OS for the remaining mutation-positive patients to 26% (P =.003). Ten of the 23 mutation-positive and 11 of the 34 mutation-negative patients received an allogeneic bone marrow transplant (BMT) in first complete remission (CR). In the mutation-positive group, the disease-free survival (DFS) for the allogeneic BMT recipients was 72% versus 23% for the 13 patients who received chemotherapy or autologous BMT (P =.01). DFS for the mutation-free patients with and without allogeneic BM transplantation was 55% and 40%, respectively (P =.38). Activating mutations in the RTK/ras signaling pathway are common in pediatric AML, and their presence may identify a population at higher risk of poor outcome who may benefit from allogeneic BM transplantation.
authors.affiliation: Fred Hutchinson Cancer Research Center, Division of Clinical Research, D4-100, 1100 Fairview Ave N, PO Box 19024, Seattle, WA 98109-1024, USA. smeshinc@fhcrc.org
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Quangeng
authors.initials: Q
authors.lastname: Zhang
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
authors.forename: William G
authors.initials: WG
authors.lastname: Woods
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Arceci
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
mesh_terms: D000293:Adolescent; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000628:therapy; D007958:Leukocyte Count; D009154:Mutation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012074:Remission Induction; D015398:Signal Transduction / Q000235:genetics; D019172:Transplantation Conditioning / Q000379:methods; D016896:Treatment Outcome
chemical_list: D020794:Receptor Protein-Tyrosine Kinases