Effect of FLT3 Inhibition on Normal Hematopoietic Progenitor Cells

Weisel, Katja; Yıldırım, Sedat; Schweikle, Eric; Kanz, Lothar; Möhle, Robert

doi:10.1196/annals.1392.020

Cited by 16 publications

(13 citation statements)

References 30 publications

(54 reference statements)

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“…These pathways most likely play critical roles in the development of anemia. One explanation for anemia with multitargeted TKIs is the action on hematopoiesis of FLT-3 and Kit blockade [20,88,89]. This probably explains some forms of macrocytosis seen during sunitinib therapy and mentioned previously [16 -20].…”

Section: Discussionmentioning

confidence: 82%

The Risk for Anemia with Targeted Therapies for Solid Tumors

et al. 2012

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Background. Anemia is a common manifestation in patients with cancer. Little is known about the frequency of and risk for anemia with targeted therapies used to treat solid tumors.Methods. We performed a meta-analysis of randomized controlled trials of solid tumors by comparing targeted therapy (alone or in combination) with standard therapy alone to calculate the incidence and relative risk (RR) for anemia events associated with these agents. Overall, 24,310 patients were included in the analysis.Results. The addition of targeted therapies to standard treatment (chemotherapy or placebo/best supportive care) increased the risk for all grades of anemia by 7%. The RR for all grades (incidence, 44%) and grades 1-2 (incidence, 38.9%) of anemia was higher with biological therapies

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Section: Discussionmentioning

confidence: 82%

The Risk for Anemia with Targeted Therapies for Solid Tumors

et al. 2012

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“…19,20 Furthermore, it has previously been shown that plasma FL levels rise during periods of bone marrow aplasia induced by chemotherapy or radiation. [21][22][23][24][25][26][27] Given that in both of these trials lestaurtinib was administered after intensive chemotherapy, we decided to examine FL levels in the plasma samples available to us.…”

Section: Plasma Flt3 Ligand Levels Are Elevated After Chemotherapymentioning

confidence: 99%

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

Sato

Yang

Knapper

et al. 2011

Blood

223

252

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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 IntroductionAcute myeloid leukemia (AML) patients who harbor the FLT3/ITD mutation have an exceptionally poor prognosis. 1,2 During the past decade, efforts have been underway to develop FLT3 inhibitors in the hopes of improving outcomes for these patients. 3 Several agents have now been studied as monotherapy for this disease, and the results have been only modestly successful. Although there have been a few remissions reported, the responses are usually limited to clearance of peripheral blasts, with persistence of disease in the marrow. In light of this, attention has turned to incorporating these agents into existing chemotherapy regimens, on the hypothesis that FLT3 inhibition will synergize with chemotherapy in inducing cytotoxicity. 4 Alternately, others have postulated that mobilizing the leukemia cells from the marrow might enhance the efficacy of FLT3 inhibition and have therefore tested FLT3 inhibitors in combination with CXCR4 inhibition. 5 Several large trials of chemotherapy administered in combination with FLT3 inhibitors are either actively accruing or have recently completed accrual. Because chemotherapy may alter the pharmacokinetics of FLT3 inhibitors and therefore affect target inhibition in vivo, we examined FLT3 inhibition in patients receiving lestaurtinib, an indolocarbazole FLT3 inhibitor, from 2 separate trials in which the agent was combined with chemotherapy. We noted a discrepancy in the degree of FLT3 inhibition, as measured by a plasma inhibitory activity assay, between the 2 groups of patients. We hypothesized that high levels of FLT3 ligand (FL), a cytokine that is known to increase after myelosuppressive therapy, could be interfering with FLT3 inhibition in these trials. We have therefore examined FL levels in response to chemotherapy and FLT3 inhibition, as well as the effect of FL levels on the efficacy of FLT3 inhibitors in vitro and in vivo. Our findings may explain why blasts in the bone marrow are more resistant to FLT3 inhibitors and furthermore have important implications both for FLT3 mutant AML as a disease as well as for efforts to incorporate FLT3 inhibitors into AML therapy. Methods ...

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“…In line, we also found decreased transcriptional activity of molecules involved in the maintenance of stem-cell fate such as FLT3 and PTEN (Table 1). Inhibition of FLT3 led to a reduction of the stem-cell pool 33 and inactivation of PTEN caused long-term decline of HSC fostering differentiation and proliferation 34 in murine models. Accordingly, gene expression levels of CD133 were lower in CML HSC compared their normal counterparts.…”

Section: The Hsc Subset Of Patients With CML Shows Impaired Migratorymentioning

confidence: 99%

The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence

et al. 2009

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We found that composition of cell subsets within the CD34 þ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34 þ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors.

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Effect of FLT3 Inhibition on Normal Hematopoietic Progenitor Cells

Cited by 16 publications

References 30 publications

The Risk for Anemia with Targeted Therapies for Solid Tumors

The Risk for Anemia with Targeted Therapies for Solid Tumors

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

The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence

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