Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: A cancer and leukemia group B study

Academic Article

Abstract

  • The FLT3 gene is mutated by an internal tandem duplication (ITD) in 20-25% of adults with acute myeloid leukemia (AML). We studied 82 adults <60 years of age with primary AML and normal cytogenetics, who received uniform high-dose therapy and found FLT3 ITD in 23 (28%) patients. When the 23 FLT3 ITD+ cases were compared with the 59 cases with wild-type (WT) FLT3, disease-free survival (DFS) was inferior (P=0.03), yet overall survival (OS) was not different (P=0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacked a FLT3 WT allele (FLT3ITD-R) as determined by PCR and loss of heterozygosity. Thus, three genotypic groups were identified: normal FLT3WT/WT, heterozygous FLT3ITD/WT, and hemizygous FLT3ITD/-. DFS and OS were significantly inferior for patients with FLT3ITD/- (P=0.0017 and P=0.0014, respectively). Although DFS and OS for FLT3WT/WT and FLT3ITD/WT groups did not differ (P=0.32 and P=0.98, respectively), OS of the FLT3ITD/- group was worse than the FLT3WT/WT (P=0.0005) and FLT3ITD/WT (P=0.008) groups. We propose a model in which FLT3ITD/- represents a dominant positive, gain-of-function mutation providing AML cells with a greater growth advantage compared with cells having the FLT3WT/WT or FLT3ITD/WT genotypes. In conclusion, we have identified the FLT3ITD/- genotype as an adverse prognostic factor in de novo AML with normal cytogenetics. A poor prognosis of the relatively young FLT3ITD/- adults (median age, 37 years), despite treatment with current dose-intensive regimens, suggests that new treatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.
  • Author List

  • Whitman SP; Archer KJ; Feng L; Baldus C; Becknell B; Carlson BD; Carroll AJ; Mr√≥zek K; Vardiman JW; George SL
  • Start Page

  • 7233
  • End Page

  • 7239
  • Volume

  • 61
  • Issue

  • 19