Our observations of independent Flt3-ITD and the detection of new Flt3-abnormalities at the time of relapse suggest that (i) Flt3-gene abnormalities may be even more important in the pathogenesis of chemotherapy-resistant AML than suggested from previous studies of newly diagnosed AML, and (ii) monitoring of minimal residual disease by using patient-specific real-time polymerase chain reaction assays for Flt3-abnormalities may not be reliable.
Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease.
These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease.
Changes in the pattern of FLT3 mutations between disease presentation and relapse restrict their value as a marker of minimal residual disease, and have significant implications for therapy.
In five out of six patients with a positive Flt3-ITD based MRD status a relapse of AML was observed in the follow up while one patient lacks a clinical relapse so far.
In five out of six patients with a positive Flt3-ITD based MRD status a relapse of AML was observed in the follow up while one patient lacks a clinical relapse so far.
This study shows that it could be possible to study the efficacy of FLT3 inhibitors using the level of minimal residual disease as a short-term end-point.
Such an approach redefined cytogenetic/genetic categories in 2 groups: (1) low-risk, including good/intermediate K-MRD(-) with 4-year RFS and OS of 58% and 73%, respectively; and (2) high risk, including poor-risk K, FLT3-ITD mutated cases, good/intermediate K-MRD(+) categories, with RFS and OS of 22% and 17%, respectively (P < .001 for all comparisons).
Multivariate analysis allowing for age, karyotype, FLT3-internal tandem duplications and white blood cell count at diagnosis showed that MRD after the first course of chemotherapy was an independent prognostic factor.
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).
Most sensitive methodology to detect MRD is molecular polymerase chain reaction (PCR) but its applicability is restricted to AML with leukemia-specific molecular targets (e.g.AML1-ETO, CBFB-MYH11, MLL, FLT-3).
Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed.