Abstract

Internal tandem duplications (ITD) of the FLT3 gene have been identified as negative prognostic marker in patients with acute myeloid leukemia (AML) exhibiting a normal karyotype. To evaluate the impact of different postremission strategies, such as high-dose cytarabine based chemotherapy (chemo), autologous (auto-SCT) or allogeneic stem cell transplantation (allo-SCT), in patients with normal karyotype and FLT3-ITD, we initiated a pooled data analysis within the prospective treatment trials AML-2/95, AML-1/99, AMLHD93, and AMLHD98A.

Methods: All patients (age 16–60 years) received two cycles of induction therapy with standard-dose cytarabine combined with etoposide and idarubicin. After a first consolidation therapy, patients were assigned to allo-SCT if an HLA-identical sibling donor was available in all four trials. In the AML-2/95 and AMLHD93 trials, all other patients were assigned to chemo, whereas in the AML-1/99 and AMLHD98A trials patients were randomized between chemo and auto-SCT. Patients were analyzed for the presence of FLT3-ITD by genomic DNA PCR and conventional gel electrophoresis. All statistical tests were stratified for the variable “study group”.

Results: Between 1993 and 2004 872 patients exhibiting a normal karyotype were registered. To date, results of FLT3 mutation analysis are available for 620 patients, and 182 (29%) exhibited an ITD. Response to induction therapy was 72% and 79% in the FLT3-ITD positive group and the FLT3-ITD negative group, respectively. After a median follow-up of 41 months, relapse-free (RFS) and overall survival (OS) were 33% versus 51% (p<0.0001) and 27% versus 46% (p<0.0001) in the FLT3-ITD positive and the FLT3-ITD negative groups, respectively. Analysis based on the availability of an HLA-matched family donor revealed a significantly better RFS (p=0.007) of 60% for patients with a donor (n=26) versus 21% for patients without a donor (n=102).

Conclusion: In AML patients with normal karyotype exhibiting a FLT3-ITD mutation who achieve CR after induction therapy, consolidation with allo-SCT seems to overcome the negative impact of FLT3-ITD on outcome.

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