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

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(12):3286-93. DOI: 10.1182/blood-2010-01-266742
Source: PubMed


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.

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    • "FLT3 upregulation has also been observed in vivo following exposure to lestaurtinib [27]. Finally, recent compelling data indicate that immunosuppresive therapy, including chemotherapy, increases circulating levels of FLT3 ligand, which may reduce the ability of TKIs to inhibit FLT3 activity [38]. Nonetheless, there is an ongoing Phase III clinical trial testing midostaurin with induction chemotherapy in newly diagnosed AML with FLT3-ITD ( "
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    • "Clinical studies that compared conventional chemotherapy without or with FLT3 inhibitor have yielded conflicting outcomes (Levis et al, 2011; Ravandi et al, 2010; Serve et al, 2010). The timing of of FLT3 inhibitor administration in relation to chemotherapy is probably a critical factor (Levis et al, 2004), where prior administration may inhibit the effects of subsequent chemotherapy (Pratz & Levis, 2008) while treatment following chemotherapy may be ineffective due to high circulating FLT3-ligand (Sato et al, 2011). In this regard, our observation of a sustainable suppression of the FLT3 clone by Sorafenib alone is especially informative as it suggests that FLT3 inhibitor has a definite and enduring role in complementing concomitant chemotherapy given for the FLT3-ITD wild type clones. "

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    • "These investigators further demonstrated that the presence of FLT3-ligand (FL) in vitro blunts the inhibition of FLT3 phosphorylation by a variety of tyrosine kinase inhibitors, including lestaurtinib , midostaurin, sorafenib, and AC220. They thus hypothesized that a dramatic rise in FL following chemotherapy may be responsible for suppressing sustained FLT3 inhibition, possibly explaining the unimpressive outcomes, to date, in clinical trials of FLT3 inhibitors combined with chemotherapy [88]. Potentially, the traditional schedule of FLT3-inhibitors given concurrently with chemotherapy may be adding toxicity without any benefit of inhibiting FLT3 due to overwhelming levels of FL. "
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