Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS-Like Tyrosine Kinase 3–Internal Tandem Duplication Status

Cortes, Jorge; Kantarjian, Hagop M.; Foran, James M.; Ghirdaladze, Darejan; Zodelava, Mamia; Borthakur, Gautam; Gammon, Guy; Trone, Denise; Armstrong, Robert C.; James, Joyce; Levis, Mark J.

doi:10.1200/jco.2013.48.8783

Cited by 318 publications

(276 citation statements)

References 29 publications

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“…In contrast, quizartinib is a potent FLT3 inhibitor (IC50 in culture medium 2 nM; in plasma 18 nM), and a modestly potent c-Kit inhibitor with an IC50 in culture medium of 28 nM. AML patients readily achieve micromolar plasma concentrations of this agent, 12 and myelosuppression was observed in leukemia patients treated with quizartinib.…”

Section: 10mentioning

confidence: 99%

Inhibition of c-Kit by tyrosine kinase inhibitors

2014

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Several small molecule tyrosine kinase inhibitors (TKIs) inhibit c-Kit, an effect associated with myelosuppression and hair depigmentation. We studied a panel of approved and investigational TKIs for inhibitory activity against FLT3 and c-Kit, and on hematopoietic progenitor cells. Potent cKit inhibitors such as dasatinib, pazopanib, and quizartinib demonstrated the greatest disruption of hematopoietic progenitor cells, while sorafenib, which has negligible activity against c-Kit, demonstrated only minimal disruption. Our data highlight the importance of determining a therapeutic index between the targeted receptor and c-Kit for TKIs used to treat malignancies in order to maintain normal hematopoiesis and improve outcomes.Myelosuppression is a common adverse event in new drug development in oncology. Many tyrosine kinase inhibitors (TKIs) have activity against c-Kit, a receptor tyrosine kinase (RTK) which is essential for normal hematopoiesis.1 The c-Kit receptor is an important marker of long-term hematopoietic stem cells, and it also plays an important role in hair and skin pigmentation. For example, the W mouse, in which the function of c-Kit is impaired, has white spots, anemia, and reduced megakorycytes, and c-Kit knockouts in transgenic mice is embryonic lethal (reviewed by Lyman and Jacobsen 1). Patients treated with TKIs that inhibit c-Kit, therefore, are at risk for myelosuppression.2 In vivo c-Kit inhibition is also associated with hair depigmentation ( Figure 1A).3 Drugs such as pazopanib and sunitinib, which have activity against c-Kit, do not induce myelosuppression in solid tumor patients when used as single agents. In contrast, dasatinib and imatinib, which also inhibit c-Kit, have been associated with myelosuppression in patients with Philadelphia-positive (Ph + ) leukemia. 4In patients with relapsed/refractory FLT3/ITD acute myeloid leukemia (AML), treatment with the FLT3 inhibitor quizartinib was associated with myelosuppression, whereas in a similar patient population, a different FLT3 inhibitor, sorafenib, induced no myelosuppression. 5,6To better understand the relationship between inhibition of c-Kit, FLT3, and marrow suppression, we studied a series of different TKIs using bone marrow progenitor cell assays and immunoblots.Cell lines were cultured as previously described. 2 TF-1 cells were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA) and grown in RPMI supplemented with GM-CSF (Invitrogen, Grand Island, NY, USA). Quizartinib was obtained from Ambit Biosciences (San Diego, CA, USA). Crenolanib was obtained from Arog Pharmaceuticals (Dallas, TX, USA). Dasatinib, pazopanib, and imatinib were obtained from LC Laboratories (Woburn, MA, USA). Electrophoresis, immunoblotting, and hematopoietic progenitor cell assays were performed as described. 2Cytokines used included SCF, G-CSF, GM-CSF, IL-3, IL-6, and erythropoietin. Unused portions of bone marrow from normal donors were collected under an institutional review boardapproved Tumor and Cell Procurement Bank at John...

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Section: 10mentioning

confidence: 99%

Inhibition of c-Kit by tyrosine kinase inhibitors

2014

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“…In contrast, low-dose sunitinib treatment showed poor anti-leukemic activity in the same model (42). In a first clinical phase I trial in refractory/ relapsed AML patients, quizartinib demonstrated promising results with response rates (CR and PR) in 10 of 76 and 13 of 76 patients, respectively (57). In a subsequent phase II study, quizartinib conferred response rates of 54% and 31% in FLT3-ITD and FLT3-WT AML patients, respectively, although rates of CR were low (58).…”

Section: Discussionmentioning

confidence: 99%

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Murone

Radpour

Attinger

et al. 2017

Molecular Cancer Therapeutics

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Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, SRC, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34þ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34 þ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses.

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“…In mouse xenograft model, quizartinib significantly extends the life span at a dose as low as 1 mg/kg daily and eradicates tumors at 10 mg/kg (75). In a phase I clinical trial, 30% patients irrespective of FLT3 mutant status showed clinical response (76). In patients with FLT3-ITD, 53% showed a clinical response compared with 14% in patients with wildtype FLT3.…”

Section: Quizartinibmentioning

confidence: 99%

Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

Chen

Pan²,

Guo

et al. 2017

Stem Cell Investig.

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Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS-Like Tyrosine Kinase 3–Internal Tandem Duplication Status

Abstract: Quizartinib has clinical activity in patients with relapsed/refractory AML, particularly those with FLT3-ITD, and is associated with an acceptable toxicity profile.

Cited by 318 publications

References 29 publications

Inhibition of c-Kit by tyrosine kinase inhibitors

Inhibition of c-Kit by tyrosine kinase inhibitors

The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

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