A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response

Pratz, Keith W.; Cortes, Jorge; Roboz, Gail J.; Rao, Niranjan; Arowojolu, Omotayo; Stine, Adam; Shiotsu, Yukimasa; Shudo, Aiko; Akinaga, Shiro; Small, Donald; Karp, Judith E.; Levis, Mark J.

doi:10.1182/blood-2008-09-177030

Cited by 158 publications

(160 citation statements)

References 41 publications

Supporting

Mentioning

157

Contrasting

Order By: Relevance

“…The total and unbound plasma concentration of sorafenib and the total plasma concentration of the sorafenib N‐oxide metabolite were measured using a liquid chromatography with tandem mass spectrometry method 24, 32. FLT3 and its downstream factor ERK ex vivo activities in TF‐1 cells expressing FLT3‐ITD were measured using Western blot, as previously described 33. FLT3 and ERK activity were reported as the percent change from baseline for each individual, with the individual baseline activity set at 100% for each patient.…”

Section: Methodsmentioning

confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.

show abstract

Section: Methodsmentioning

confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because it has been suggested that complete and enduring inhibition of FLT3 phosphorylation is critical for achieving clinical efficacy (40,41), failure to completely inhibit FLT3 may contribute to persistence of leukemic progenitors after treatment. However, to our knowledge, it has not yet been definitively shown that complete inhibition of FLT3 actually translates into improved clinical outcome in FLT3-ITD þ AML.…”

Section: Discussionmentioning

confidence: 99%

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

et al. 2011

View full text Add to dashboard Cite

Targeting constitutively activated FMS-like tyrosine kinase 3 [(FLT3); FLT3-ITD] with tyrosine kinase inhibitor (TKI) in acute myeloid leukemia (AML) leads to clearance of blasts in the periphery but not in the bone marrow, suggesting a protective effect of the marrow niche on leukemic stem cells. In this study, we examined the effect of stromal niche cells on CD34 þ progenitors from patients with FLT3-ITD þ or wild-type FLT3 (FLT3-WT) AML treated with the TKIs SU5614 or sorafenib. TKIs effectively and specifically inhibited FLT3 and increased the fraction of undivided progenitors in both FLT3-ITD þ and FLT3-WT samples. Treatment with SU5614 and sorafenib also reduced the number of mature leukemic progenitors, whereas contact with stroma protected against this cell loss. In contrast, primitive long-term progenitors from both FLT3-ITD þ and FLT3-WT AML were resistant to TKIs. Additional contact with niche cells significantly expanded long-term FLT3-ITD þ but not FLT3-WT progenitors in the presence of SU5614 but not that of sorafenib. Thus, TKIs with first-generation inhibitors fail to eradicate early leukemic stem/progenitor cells in FLT3-ITD þ AML. Further, we defined a specific interaction between FLT3-ITD þ progenitors and niche cells that enables the maintenance of leukemic progenitors in the presence of TKI. Collectively, our findings suggest that molecular therapy may have unpredicted effects on leukemic progenitors, underscoring the necessity of developing strategies to selectively eliminate the malignant stem cell clone. Cancer Res; 71(13); 4696-706. Ó2011 AACR.

show abstract

“…Investigated in Phase I and II clinical trials for AML patients that are not candidates for approved therapy is KW-2449 (Pratz and Levis, 2008;Pratz et al, 2009;Shiotsu et al, 2009), for the purpose of determining its maximum tolerated dose. In a Phase I trial, KW-2449 treatment led to transient decreases in peripheral blast counts (Cortes et al, 2008;Pratz and Levis, 2008;Pratz et al, 2009 (Fiedler et al, 2005;Kancha et al, 2007;O'Farrell et al, 2003a, b), as well as the piperazinyl quinazoline MLN518 (tandutinib; CT53518; Millennium, Cambridge, MA, USA) (Kelly et al, 2002b;Cheng and Paz, 2008).…”

Section: Kinase Inhibitors Under Clinical Investigation For Mutant Flmentioning

confidence: 99%

“…In a Phase I trial, KW-2449 treatment led to transient decreases in peripheral blast counts (Cortes et al, 2008;Pratz and Levis, 2008;Pratz et al, 2009 (Fiedler et al, 2005;Kancha et al, 2007;O'Farrell et al, 2003a, b), as well as the piperazinyl quinazoline MLN518 (tandutinib; CT53518; Millennium, Cambridge, MA, USA) (Kelly et al, 2002b;Cheng and Paz, 2008). There is presently an ongoing Phase I/II trial investigating SU11248 combined with standard chemotherapy in mutant FLT3-positive AML patients over the age of 60 years.…”

Section: Kinase Inhibitors Under Clinical Investigation For Mutant Flmentioning

confidence: 99%

“…Generally, FLT3 inhibitors tested thus far clinically induce only partial and transient responses in patients when used as single agents. As an example, Phase I testing of KW-2449 showed only transient inhibition of FLT3 in patients to o20% of baseline (Pratz et al, 2009). It is anticipated that the limited clinical efficacy of FLT3 inhibitors may be due to their inability to elicit sustained, complete responses in patients (Chu and Small, 2009).…”

Section: Causes Of Resistance To Flt3 Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Drug resistance in mutant FLT3-positive AML

et al. 2010

View full text Add to dashboard Cite

Mutant Fms-Like Tyrosine kinase-3 (FLT3), which is expressed in the leukemic cells of a subpopulation of acute myeloid leukemia (AML) patients, represents an attractive target for the therapy of AML. There are several FLT3 inhibitors presently in clinical trials with sufficient efficacy and toxicity features to warrant further testing in combination with standard therapies. However, the transient and partial responses observed in AML patients treated with FLT3 inhibitors, coupled with the discovery of drug-resistant leukemic blast cells in AML patients, have made resistance to FLT3 inhibitors a growing concern. In this study, we provide an overview of the role of mutant FLT3 in AML, FLT3 inhibitors under clinical and preclinical investigation, mechanisms of resistance to FLT3 inhibitors, and possible therapeutic approaches to overcoming this resistance.

show abstract

A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response

Cited by 158 publications

References 41 publications

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Stromal Niche Cells Protect Early Leukemic FLT3-ITD+ Progenitor Cells against First-Generation FLT3 Tyrosine Kinase Inhibitors

Drug resistance in mutant FLT3-positive AML

Contact Info

Product

Resources

About