Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia.
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.
Meshinchi
Soheil
S
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
Stirewalt
Derek L
DL
Alonzo
Todd A
TA
Zhang
Quangeng
Q
Sweetser
David A
DA
Woods
William G
WG
Bernstein
Irwin D
ID
Arceci
Robert J
RJ
Radich
Jerald P
JP
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
D020794:Receptor Protein-Tyrosine Kinases