FLT3 Mutations in a Large Series of Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid and Anthracycline Monochemotherapy.

Background: The prognostic significance of FLT3 internal tandem duplication (ITD) and D835 mutations in acute promyelocytic leukemia (APL) remains unclear. Recent studies have revealed an association between FLT3 mutations and leukocytes > 10x10⁹/L, M3-variant subtype and BCR3 isoform. It has been also suggested that patients with FLT3 mutations have a higher induction death rate and a shorter survival. Objectives: To analyze in patients with newly diagnosed APL treated with an ATRA plus anthracycline-based protocol if the presence of FLT3 ITD and D835 mutations influences the clinical and biological presenting features, and the disease outcome.

Material and methods: Between 1997 and 2005, 733 consecutive patients were enrolled in the PETHEMA LPA96 and LPA99 trials. Treatment consisted of Induction therapy with oral ATRA (45 mg/m²/d) and intravenous idarubicin (12 mg/m²/d x 4 days) followed by three courses of consolidation with anthracycline monochemotherapy. In the LPA99 trial, ATRA was added in each cycle of consolidation for intermediate and high risk patients (according to Sanz score). In both trials, maintenance therapy consisted of intermittent ATRA and low dose chemotherapy with methotrexate and 6-mercaptopurine. Using RT-PCR, analysis of the FLT3 ITD and D835 mutations was available in 251 and 191 patients respectively.

Results: Overall, 61 patients (24%) had a FLT3 ITD mutation and 20 patients (10%) had a FLT3 D835 mutation. Only one patient had both mutations. FLT3 ITD was associated with BCR3 isoform (78% vs 32%, p < 0.01), leukocytes > 10x10⁹/L (64% vs 17%, p < 0.01), M3v subtype (46% vs 13%, p < 0.01), bone marrow blasts > 70% (95% vs 80%, p < 0.01) and expression of CD2 and CD34 surface antigens (41% vs 14% and 38% vs 9%, respectively, p < 0.01). FLT3 D835 was not associated with leukocytes > 10x10⁹/L (35% vs 25%, p=0.31) or any other biological characteristic. There was a trend towards a higher induction death rate in patients with FLT3 ITD or D835 mutations, when compared to patients with wild-type FLT3 (15% vs 16% vs 6%, respectively, p=0.08). There was no significant difference on relapse-free survival (RFS) and overall survival (OS) at 7 years in patients with FLT3 ITD, when compared to those with FLT3 D835 or wild-type FLT3 (81% vs 100% vs 87% for RFS, p=0.17; and 76% vs 84% vs 81% for OS, p=0.37).

Conclusion: In a large cohort of patients with newly diagnosed APL, the incidence of FLT3 ITD and FLT3 D835 mutations was 24% and 10%. This study was only able to demonstrate an association of FLT3 ITD with leukocytes > 10x10⁹/L, M3v subtype, BCR3 isoform, and expression of CD2 and CD34 surface antigens, but this mutation had no independent prognostic value in patients with APL receiving state-of-the-art treatment.