Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse

Abstract

Analysis of internal tandem duplications of FLT3 (FLT3/ITD) was performed on bone marrow samples obtained at diagnosis and relapse from 108 adult patients with de novo acute myeloid leukemia (AML) to determine the role of this mutation in leukemic relapse. Eighty-three patients had wild-type FLT3 at both diagnosis and relapse, 16 had FLT3/ITD at both stages, whereas 8 had acquired the mutation and 1 had lost it at relapse. Using Genescan analysis, we found that FLT3/ ITD levels at first relapse were significantly higher than those at diagnosis (mean ؎ SE, 40.5% ؎ 4.8% versus 17.9% ؎ 3.6%, P < .001). The increase in mutation levels at relapse as compared with diagnosis did not correlate with the difference in blast cell percentages at both stages (P ‫؍‬ .777). A hemizygous deletion of wild-type FLT3 was found in 4 patients at relapse compared to none at diagnosis. Nine of the 11 patients carrying a single mutation at diagnosis relapsed with an identical mutation. All 6 patients with more than one FLT3/ ITD mutation at diagnosis showed changes in mutation patterns and levels at first relapse; however, each patient retained at least one mutation in the relapse sample. The changes of mutation patterns had implications for the monitoring of minimal residual disease. Our results suggest that FLT3/ITD may contribute as the initial transforming event in AML, and relapse can reflect the selection and outgrowth of a mutant clone or evolution of a new clone harboring this mutation. (Blood.

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

“…One possibility is that FLT3 mutations may emerge owing to the instability of the tumor genome. 24,25 The higher frequency of cytogenetic clonal evolution known to be associated with FLT3 mutations found in this study potentially supports this possibility. A second possibility is that, leukemia cells with FLT3 mutations may be present in bone marrow at time of initial diagnosis in a very small number that is below the level of detection of the assays to assess FLT3.…”

“…Several studies have observed FLT3 mutation status changes in small subsets of acute myeloid leukemia patients and have implied the prognostic importance. 10,16,[21][22][23][24][25][26][27][28][29] In aggregate, these data suggest that gain of FLT3 mutations may be associated with worse prognosis. 24,27,29,33 These patients also seem not to benefit from intensifying chemotherapy.…”

“…10,16,[21][22][23][24][25][26][27][28][29] One previous study reported that FLT3-ITD is more often acquired than FLT3-TKD at time of relapse, 8% and 2%, respectively, whereas FLT3-TKD is more often lost Change of FLT3 mutation status in acute myeloid leukemia M Warren et al than FLT3-ITD, 7% and 4%, respectively. 29 In our study, FLT3 mutations were acquired far more often than lost, in a ratio of 6 to 1, during the disease course.…”

“…10,16,[21][22][23][24][25][26][27][28][29] However, owing to a lack of a sufficient number of patients, no study has been able to provide statistical significant correlations between FLT3 status changes and disease progression. The goal of this study is to examine the clinical features and outcome of a large cohort of acute myeloid leukemia patients in whom FLT3 mutation status changed.…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…Among these, allele burden of FLT3-ITD is a key predictor of response to FLT3 inhibitor therapy. 79,80 In vitro studies of FLT3-ITDpositive cell lines demonstrated that relapsed samples and samples with a high mutant allele burden were more likely to be responsive to cytotoxicity from FLT3 inhibition compared with the samples obtained at diagnosis or those with a low mutant allele burden. 78 In these samples with lower FLT3-ITD allele burden, inhibition of FLT3 activity frequently did not result in cell death, suggesting that AML in patients with earlier stage disease and lower FLT3-ITD allele burden may not be addicted to FLT3 signaling for survival and proliferation.…”