FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

Takashi Sato, Xiaochuan Yang, Steven Knapper, Paul White, B. Douglas Smith, Steven Galkin, Donald Small, Alan Burnett, Mark Levis

Research output: Contribution to journalArticlepeer-review

Abstract

We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)3286-3293
Number of pages8
JournalBlood
Volume117
Issue number12
DOIs
StatePublished - Mar 24 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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