FLT3 Mutations in Normal Karyotype Acute Myeloid Leukemia in First Complete Remission Treated with Autologous Peripheral Blood Stem Cell Transplantation.

Abstract

Two types of activating FLT3 mutations have been described in AML. FLT3/ITDs can be detected in 20% to 30% of patients with AML. Point mutations of FLT3/D835 have been described in 7% of adult AML patients. Activating FLT3 mutations has been associated with the leukocytosis and poor prognosis. We retrospectively analyzed the significance of FLT3 mutations in AML patients of normal karyotype treated with autologous peripheral blood stem cell transplantation (auto-PBSCT).METHOD: We evaluated 34 consecutive patients with first CR AML of normal karyotype who received myeloablative therapy and auto-PBSCT to analyze clinical features and outcomes between patients with and without FLT3/ITDs and FLT3/D835. There were 16 males and 18 females with a median age of 41.5 years ranging 15–74 years. Cytogenetic G-banding analysis was performed with standard method. The distribution of morphologic types of AML according to the FAB classification was as follows; one patient was M0, twelve M1, eight M2, seven M4 and six M5. The pre-transplant conditioning regimen was G-CSF combined with the high-dose chemotherapy consisting of busulfan (16 mg/kg), etoposide (40 mg/kg) and Ara-C (3 g/m2x4) (BEA regimen). DNA PCR assay was used to detect FLT3/ITDs. All abnormal longer products by agarose gel electrophoresis were subsequently sequenced. DNA PCR assay followed by direct sequence were used to detect FLT3/D835.RESULT: FLT3/ITDs were detected in 8 of 34 patients (23.5 %). FLT3 D835 mutation was detected in 2 of 34 patients (5.9%). To define clinical differences between patients with and without FLT3/ITDs, clinical variables at the diagnosis were compared. WBC (p=0.013), LDH (p=0.0147), the percentage of PB and BM blasts (p=0.0422 and P=0.0021) were significantly higher in the FLT3/ITDs patients. Other clinical parameters such as age, sex, FAB classification, Hb, Plt, remission induction therapy, interval from diagnosis to auto-PBSCT, number of infused CD34+ cells and hematological recovery after auto-PBSCT are not associated with the presence or absence of FLT3/ITDs. We analyzed the clinical significance of FLT3/ITDs mutations. OS and DFS was similar in patients with or without FLT3/ITDs (5 years OS, 71.4% vs 78.9%, p=0.5746; 5 years DFS, 72.9% vs 68.6%, p=0.9273 by the log-rank test).DISCUSSION: As far as we know, this is the first report to describe the significance of FLT3 mutations in AML patients of normal karyotype treated with auto-PBSCT. We show that FLT3 mutations have no prognostic impact in autotransplanted AML 1CR patients of normal karyotype. Our data suggest dose escalation of chemotherapy may conquer the poor prognostic implications of FLT3 mutations. The prognostic significance of activating FLT3 mutations in AML patients with normal karyotype should be evaluated in relation with post-remission therapeutic modalities.