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

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-f ree survival (DFS) was inferior (P = 0.03), yet overall survival (OS) was n ot different (P = 0.14). However, 8 (35%) of 23 FLT3 ITD/+ cases also lacke d a FLT3 WT allele (FLT3(ITD-R)) as determined by PCR and loss of heterozyg osity. Thus, three genotypic groups were identified: normal FLT3(WT/WT), he terozygous FLT3(ITD/WT), and hemizygous FLT3(ITD/-). DFS and OS were signif icantly inferior for patients with FLT3(ITD/-) (P = 0.0017 and P = 0.0014, respectively). Although DFS and OS for FLT3(WT/WT) and FLT3(ITD/WT) groups did not differ (P = 0.32 and P = 0.98, respectively), OS of the FLT3(ITD/-) group was worse than the FLT3(WT/WT) (P = 0.0005) and FLT3(ITD/WT) (P = 0. 008) groups. We propose a model in which FLT3(ITD/-) represents a dominant positive, gain-of-function mutation providing AML cells with a greater grow th advantage compared with cells having the FLT3(WT/WT) or FLT3(ITD/WT) gen otypes. In conclusion, we have identified the FLT3(ITD/-),genotype as an ad verse prognostic factor in de novo AML with normal cytogenetics. A poor pro gnosis of the relatively young FLT3(ITD/-) adults (median age, 37 years), d espite treatment with current dose-intensive regimens, suggests that new tr eatment modalities, such as therapy with a FLT3 tyrosine kinase inhibitor, are clearly needed for this group of patients.