Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples

Abstract

In acute myeloid leukemia (AML), activating mutations in the fms-like tyrosine kinase 3 (FLT3) gene predict poor prognosis. We determined FLT3 internal tandem duplications (FLT3/ITD) and D835 point mutations in paired initial and relapse samples from 80 pediatric and adult AML patients. One D835 point mutation was found in an initial pediatric AML sample. Fms-like tyrosine kinase 3/ITDs were present in 21 initial and 22 relapse samples (26.3 and 27.5%, respectively). Interestingly, FLT3/ITD positivity was related to a significantly shorter time to relapse, most pronounced when the ITD-positive status was found at relapse (Po0.001). However, FLT3/ITD status changed between diagnosis and relapse in 14 cases. In four patients, the FLT3/ITD became undetectable at relapse in five patients FLT3/ITDs were only detected at relapse, and in five patients the length or number of FLT3/ITDs changed. Gain of FLT3/ITDs may suggest oligoclonality with selective outgrowth of the FLT3/ITD-positive clone, whereas losses may reflect ITDs in the more mature leukemic cells rather than in the leukemic stem cell, or, alternatively, that other genetic aberrations provided a greater selective advantage. Studying FLT3/ITD kinetics in minimal residual disease setting may provide some answers for the changes we observed. Fms-like tyrosine kinase 3/ITD is a relevant marker for prognosis, and remains an important target for therapeutic inhibition.

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

“…FLT3 mutation testing will not be useful as an MRD marker in patients who lose their FLT3 mutation; however, these patients have better OS and a longer time to relapse than patients who gain or retain FLT3 mutations. 26,27 In line with reported studies by us and others, 28-30 the presence of MRD by flow cytometry might be associated with a lower OS after alloHCT regardless of FLT3-ITD mutation status; however, considerable caution should be exercised given that only a very small number of patients had MRD positivity.…”

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

“…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.…”

SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants

“…3,5 The identification of asymptomatic patients at diagnosis that may benefit from initial watch and wait approach is challenging because some studies have shown that intensive treatment may improve the survival of patients with MCL. 8 Therefore, it is of paramount importance to develop clinical and biological criteria that may assist in the selection of the optimal individual management for patients with MCL.…”