Impact of FLT3 internal tandem duplications on Indian acute promyelocytic leukemia patients: Prognostic implications

Abstract

Despite recent advances in the treatment of acute promyelocytic leukemia (APL), early mortality and relapses still occur. With the view to evaluate the role of FLT3 mutation in APL, 54 patients (median age 28 years, range11-57 years, male to female ratio 1.2:1, median TLC 8.4 x 10(9)/l, range 1-170 x 10(9)/l) were studied by reverse transcriptase-PCR. Forty-two patients (77%) achieved first remission (CR1). Ten (18.5%) of the 54 patients had internal tandem duplication of exons 11 and 12 of the FLT3 gene. The median TLC count was significantly higher in FLT3 positive cases (Median TLC 55.0 x 10(9)/l) as compared to FLT3 negative cases (Median TLC 6.8 x 10(9)/l) (p = 0.001). Induction CR was much lower (40%) in FLT3/ITD positive cases as compared to 86% of FLT3/ITD negative cases (p = 0.005). Early deaths too were significantly associated with FLT3/ITD positive cases (50 vs. 16% p = 0.033). The difference in the occurrence of bcr1 and bcr3 isoforms was not statistically significant between the two groups. The data suggest that the presence of FLT3/ITD in APL patients confers a poor prognosis.

Prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy

“…As previously reported, 11,13,14,33 patients with ITD had an increased risk of induction death also in our study. However, the multivariate analysis made clear that this was due to the association with hyperleukocytosis, a wellestablished risk factor for induction death.…”

“…Activating mutations of FLT3 have been reported in APL at frequencies within the range of 12% to 39% for FLT3-ITD (median 21%), [5][6][7][8][9][10][11][12][13][14][15]17,33,34 and 6% to 22% for FLT3-D835 (median 9%). [6][7][8][9][10][11][12]14,15,17 The incidence of these mutations in our Prognostic value of FLT3 mutations in APL haematologica | 2011; 96 (10)study, 22% and 9%, respectively, are consistent with the reported data.…”

“…3,4 However, the prognostic value of FLT3 mutations in patients with acute promyelocytic leukemia (APL), a form of acute myeloid leukemia characterized by the specific t (15;17), is still a matter of controversy. Although several studies in APL have reported an association between FLT3-ITD and various characteristics, including elevated white blood cell (WBC) count, BCR3 isoform, and microgranular morphology (M3v), [5][6][7][8][9][10][11][12][13][14][15] the prognostic value of these mutations remains to be established. Two previous studies used multivariate analysis including both WBC count, a well-known poor risk factor in APL, 16 and ITD in order to assess the independent value of each one.…”

Comprehensive FLT3 analysis in Indian acute myeloid leukaemia

“…Surface FLT3 receptor protein (CD135) was studied on intact leukemic blasts using bone marrow or peripheral blood samples, by flow cytometric analysis along with immunophenotypic study as described earlier [17].…”

“…Various study groups including few Indian studies have reported the association of activating mutations of FLT3 ITD, with the poor clinical outcome in AML patients [5,[14][15][16][17][18], with only few studies reporting absence of association of FLT3 ITD with disease prognosis [19,20].…”