[Prevalence and clinical significance of FLT3 mutations in acute promyelocytic leukemia].

OBJECTIVE

To evaluate the prevalence of Fms-Like tyrosine kinase 3 (FLT3) mutations including internal tandem duplication (ITD) of juxtamembrane region and point mutation in the second tyrosine kinase domain (TKD) in acute promyelocytic leukemia (APL) and its clinical significance.

METHODS

Bone marrow mononuclear cells from 160 newly diagnosed APL patients were analyzed. Polymerase chain reaction (PCR) was used to detect FLT3-ITD mutations, FLT3-ITD positive samples were further analyzed for the ITD allelic ratio (ITD-AR, mutant-wild type ratio). The FLT3-TKD mutation was analyzed by PCR amplification of exon 20 followed by EcoR V digestion and sequencing.

RESULTS

Out of 160 patients, 30 (18.75%) patients were FLT3-ITD positive, 17 (10.62%) were FLT3-TKD positive, 2 had both of mutations. The initial WBC count and the ratio of short type PML-RAR alpha isoforms in FLT3-ITD positive and FLT3-TKD positive patients were all higher than that in patients with wild-type FLT3 (FLT3-wt) (P < 0.05). For FLT3-ITD positive patients, the incidences of retinoic acid syndrome (RAS) and disseminated intravascular coagulation (DIC) were 41.7% and 65.4%, respectively, being higher than that of FLT3-wt patients, while their complete remission (CR) rate was lower (69.2% vs 90.3%, P < 0.05). For FLT3-TKD positive patients, the incidence of RAS, DIC and CR rate were not significantly different from that of FLT3-wt patients (P > 0.05). FLT3-ITD positive patients had a shorter overall survival (OS) (P < 0.05), but not disease-free survival (DFS) (P > 0.05) as compared with FLT3-wt patients. There was no significant difference in either OS or DFS between FLT3-TKD positive and FLT3-wt patients. The ITD-AR of 30 FLT3-ITD positive patients varied from 0.11 to 6.55 with a median of 1.0. The initial WBC count, incidence of RAS and DIC, CR rate were not significantly different between the patients with ITD-AR greater than 1.0 and lower than 1.0 (P > 0.05).

CONCLUSIONS

FLT3 mutations (FLT3-ITD or FLT3-TKD) are frequently identified in patients with newly diagnosed APL, both mutations are associated with higher initial WBC and short type PML-RAR alpha isoforms. FLT3-ITD mutation is more frequent than FLT3-TKD mutation, and predicts a poorer prognosis, whereas FLT3-TKD mutation does not show the same unfavorable prognostic effect on APL patients.