Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

Abstract

The online version of this article has a Supplementary Appendix. BackgroundCombined treatment with all-trans-retinoic acid and chemotherapy is extremely efficient in patients with acute promyelocytic leukemia with t(15;17)/PML-RARA, but up to 15% of patients relapse. Design and MethodsTo further clarify the prognostic impact of parameters such as FLT3 mutations, we comprehensively characterized the relation between genetic features and outcome in 147 patients (aged 19.7-86.3 years) with acute promyelocytic leukemia. ResultsInternal tandem duplications of the FLT3 gene (FLT3-ITD) were detected in 47/147 (32.0%) and tyrosine kinase domain mutations (FLT3-TKD) in 19/147 (12.9%) patients. FLT3-ITD or FLT3-TKD mutation status did not have a significant prognostic impact, whereas FLT3-ITD mutation load, as defined by a mutation/wild-type ratio of less than 0.5 was associated with trends to a better 2-year overall survival rate (86.7% versus 72.7%; P=0.075) and 2-year event-free survival rate (84.5% versus 62.1%, P=0.023) compared to the survival rates of patients with a ratio of 0.5 or more. Besides the t(15;17), an additional chromosomal abnormality was detected in 57 of 147 cases and did not show a significant impact on survival. White blood cell counts of 10¥10 9 /L or less versus more than 10¥10 9 /L were associated with a better 2-year overall survival rate (88.3% versus 69.4%, respectively; P=0.015), as was male sex (P=0.040). In multivariate analysis, only higher age had a significant adverse impact. ConclusionsProspective trials should further investigate the clinical impact of the FLT3-ITD/wild-type mutation load aiming to evaluate whether this parameter might be included in risk stratification in patients with acute promyelocytic leukemia.

Comprehensive FLT3 analysis in Indian acute myeloid leukaemia

“…In addition, among hematological parameters significant association of FLT3 ITD was confirmed with higher blast count as seen in other studies [15,19,23] as well as with low platelet count which has also been shown by the study of Schnittger et al [41] on APL patients. In relation to AML FAB subtypes, high incidence of FLT3 ITD was noted in AML M6 (50%) followed by M1 (30%), M5b (29%), M3 (25%) while low incidence was noted in M2, M4 and M5a though difference was not significant.…”

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

“…4,10 However, after adjustment for the associated WBCs by multivariate analysis (WBC Ն 10 000/L being the most consistent indicator of increased relapse risk after ATRA/CT therapy 11 ), the independent prognostic significance of the S-isoform and/or FLT3-ITD ϩ has most often been lost or marginalized. 3,8,10,[12][13][14] Similarly, in some ATRA/CT trials, ACAs at diagnosis were associated with increased relapse risk by univariate but not multivariate analysis. 8,10,15 In protocol C9710, patients analyzed at diagnosis for FLT3 mutations and ACAs, the only association with reduced disease-free survival (DFS) was a complex karyotype (Ն 2 ACAs; X.P.…”

FLT3-ITD confers poor prognosis in patients with acute promyelocytic leukemia treated with AIDA protocols: long-term follow-up analysis

“…12 A German study found that patients with FLT3 mutation/wild-type ratio of 0.5 or over had better 2-year OS and EFS rates compared to patients with a ratio less than than 0.5. 13 In the PETHEMA/HOVON experience, 14 in univariate analysis FLT3-ITD mutations were associated to higher relapse and lower OS not retained in multivariate analysis, probably due to a shorter median follow up. A Korean group also showed a higher relapse rate in FLT3-ITD + patients with respect to those FLT3-negative.…”