Reference Detail

Ref Type

Journal Article

PMID

(35344039)

Authors

Inaba H, van Oosterwijk JG, Panetta JC, Li L, Buelow DR, Blachly JS, Shurtleff S, Pui CH, Ribeiro RC, Rubnitz JE, Pounds S, Baker SD

Title

Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	28	12	2022 Jun 13	2536-2546	Clin Cancer Res

URL

Abstract Text

To evaluate the safety, activity, and emergence of FLT3-kinase domain (KD) mutations with combination therapy of crenolanib and sorafenib in acute myeloid leukemia (AML) with FLT3-internal tandem duplication (ITD).After in vitro and xenograft efficacy studies using AML cell lines that have FLT3-ITD with or without FLT3-KD mutation, a pilot study was performed with crenolanib (67 mg/m2/dose, three times per day on days 1-28) and two dose levels of sorafenib (150 and 200 mg/m2/day on days 8-28) in 9 pediatric patients with refractory/relapsed FLT3-ITD-positive AML. Pharmacokinetic, pharmacodynamic, and FLT3-KD mutation analysis were done in both preclinical and clinical studies.The combination of crenolanib and sorafenib in preclinical models showed synergy without affecting pharmacokinetics of each agent, inhibited p-STAT5 and p-ERK for up to 8 hours, and led to significantly better leukemia response (P < 0.005) and survival (P < 0.05) compared with single agents. Fewer FLT3-KD mutations emerged with dose-intensive crenolanib (twice daily) and low-intensity sorafenib (three times/week) compared with daily crenolanib or sorafenib (P < 0.05). The crenolanib and sorafenib combination was tolerable without dose-limiting toxicities, and three complete remissions (one with incomplete count recovery) and one partial remission were observed in 8 evaluable patients. Median crenolanib apparent clearance showed a nonsignificant decrease during treatment (45.0, 40.5, and 20.3 L/hour/m2 on days 1, 7, and 14, respectively) without drug-drug interaction. Only 1 patient developed a FLT3-KD mutation (FLT3 F691L).The combination of crenolanib and sorafenib was tolerable with antileukemic activities and rare emergence of FLT3-TKD mutations, which warrants further investigation.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
FLT3	G846C	missense	unknown	FLT3 G846C lies within the protein kinase domain of the Flt3 protein (UniProt.org). G846C has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 35344039), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Mar 2024).	Y
FLT3	V843I	missense	unknown	FLT3 V843I lies within the protein kinase domain of the Flt3 protein (UniProt.org). V843I has been demonstrated to promote secondary drug resistance in the context of FLT3 internal tandem duplication (FLT3-ITD) mutations (PMID: 35344039), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, Mar 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FLT3 exon 14 ins FLT3 V843A	acute myeloid leukemia	resistant	Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 V843A was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Nexavar (sorafenib) when administered once daily or 3 days per week (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835H	acute myeloid leukemia	resistant	Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835H was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	resistant	Crenolanib + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835Y was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on the combination of Crenolanib (CP-868596) and Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 N841K	acute myeloid leukemia	resistant	Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 N841K was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835N	acute myeloid leukemia	resistant	Crenolanib + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835N was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on the combination of Crenolanib (CP-868596) and Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	resistant	Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835Y was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835A	acute myeloid leukemia	resistant	Crenolanib + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835A was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on the combination of Crenolanib (CP-868596) and Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	conflicting	Crenolanib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835Y was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Crenolanib (CP-868596) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 F691L	acute myeloid leukemia	resistant	Crenolanib + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 F691L was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on the combination of Crenolanib (CP-868596) and Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Crenolanib + Sorafenib	Clinical Study	Actionable	In a clinical study, combination Nexavar (sorafenib) and Crenolanib (CP-868596) resulted in 2 complete remissions, 1 complete remission with incomplete blood count recovery, and 1 partial response of 8 evaluable pediatric patients with relapsed or refractory FLT3 ITD-positive acute myeloid leukemia, and in preclinical studies, resulted in synergy in cell culture and improved leukemia response and survival in xenograft models compared to either agent alone (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 G846C	acute myeloid leukemia	resistant	Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 G846C was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 D835H	acute myeloid leukemia	resistant	Crenolanib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 D835H was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Crenolanib (CP-868596) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 N841Y	acute myeloid leukemia	resistant	Crenolanib + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 N841Y was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on the combination of Crenolanib (CP-868596) and Nexavar (sorafenib) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 V843I	acute myeloid leukemia	resistant	Crenolanib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 V843I was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on Crenolanib (CP-868596) (PMID: 35344039).	35344039
FLT3 exon 14 ins FLT3 N841K	acute myeloid leukemia	resistant	Crenolanib + Sorafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, FLT3 N841K was identified as a secondary resistance mutation in FLT3 ITD-positive acute myeloid leukemia cell line xenograft models that progressed on the combination of Crenolanib (CP-868596) and Nexavar (sorafenib) (PMID: 35344039).	35344039