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. 2006 Jul;20(7):1217-20.
doi: 10.1038/sj.leu.2404246. Epub 2006 Apr 27.

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

J Cloos  1 , B F Goemans, C J Hess, J W van Oostveen, Q Waisfisz, S Corthals, D de Lange, N Boeckx, K Hählen, D Reinhardt, U Creutzig, G J Schuurhuis, Ch M Zwaan, G J L Kaspers
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Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples

J Cloos et al. Leukemia. 2006 Jul.

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 (P<0.001). 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.

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