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

J. Cloos, 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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152 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1217-1220
Number of pages4
JournalLeukemia
Volume20
Issue number7
DOIs
Publication statusPublished - Jul 2006
Externally publishedYes

Keywords

  • Acute myeloid leukemia
  • FLT3
  • Paired samples

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