Patient‐specific analysis of FLT3 internal tandem duplications for the prognostication and monitoring of acute myeloid leukemia

Abstract

Objectives Internal tandem duplications (ITDs) of the fms‐like tyrosine kinase 3 ( FLT3) gene occur in 13–35% of patients with acute myeloid leukemia (AML). FLT3‐ITD is associated with poor clinical outcome and is an indication for allogeneic stem cell transplantation (allo‐SCT). Methods To investigate FLT3‐ITD length, position, and mutational load in AML cases, we developed patient‐specific quantitative real‐time reverse transcription polymerase chain reaction (qRT‐PCR) assays and correlated the results with established sensitive minimal residual disease (MRD) parameters and clinical outcome. Results In 409 patients with AML, FLT3‐ITDs could be detected in 54 cases (13%). Within our cohort, patients with FLT3‐ITD ≥45 base pairs had significantly higher relapse rates (P = 0.03) and a worse overall survival (P = 0.03). Our method could be applied to 97% of FLT3‐ITD‐positive patients and was as sensitive as other MRD parameters such as PML‐RARA , NPM1 mutations, or MLL ‐PTD (correlation: r = 0.63; 0.99, and 0.99, respectively). MRD negativity predicted lasting remission independent of allo‐SCT (N = 7) or non‐allo‐SCT (N = 9). All paired diagnostic/relapsed samples showed FLT3‐ITD positivity. Compared with bone marrow samples, FLT3‐ITD analyses appeared to be equivalently sensitive in peripheral blood. Conclusions We conclude that individualized monitoring of FLT3‐ITD in patients with AML may guide treatment decisions and should be evaluated for the indication for allo‐SCT.

Umbilical cord blood transplantation is a suitable option for consolidation of acute myeloid leukemia with FLT3-ITD

“…20,21 Using FLT3 mutation as an MRD marker has not been standardized or demonstrated in large studies; however, several small studies have suggested that FLT3 mutations may be useful as an MRD marker, especially when sensitive methods are employed. [22][23][24][25] In our limited numbers, FLT3-ITD mutations was negative in all tested patients while some of them had residual disease by other meth- …”

Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

“…Patients with FLT3-TKD mutations on D835 indeed had a reduced response to these two drugs (48,97). Furthermore, within patients containing FLT3-ITD mutations, the location and length of ITD also affect the sensitivity to FLT3 inhibitor treatment of FLT3 inhibitors (32,33,98,99). Patients with ITD reaching to the TKD away from the JM domain are known to have a poor prognosis for the induction chemotherapy (32,33).…”

Targeting the FLT3 Mutation in Acute Myeloid Leukaemia

“…Whereas NPM1 has been shown to be a reliable marker for minimal residual disease patient-specific primers, aim to improve the sensitivity of FLT3-ITD. 67 However, this approach has limitations, since each FLT3-ITD mutation needs a clone-specific primer/probe set, which is time-consuming and may not be possible in every case. In addition, direct sequencing may not be possible in patients with a low allelic ratio since the wild-type sequence is competitively amplified.…”