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: 10.43). 03/2011; 117(12):3286-93. DOI: 10.1182/blood-2010-01-266742
Source: PubMed

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.

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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. "
    British Journal of Haematology 11/2011; 157(1). DOI:10.1111/j.1365-2141.2011.08910.x · 4.96 Impact Factor
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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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    ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.
    01/2011; 1(2):175-89.
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    ABSTRACT: In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 μM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at as #NCT00079482.
    Blood 03/2011; 117(12):3294-301. DOI:10.1182/blood-2010-08-301796 · 10.43 Impact Factor
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