ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Preclinical and Pilot Study of Type I FLT3 Tyrosine Kinase Inhibitor, Crenolanib, with Sorafenib in Acute Myeloid Leukemia and FLT3-Internal Tandem Duplication.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed, 11 citations in OpenAlex.
- The Ethnobotanical Heritage ofPlants (Basel, Switzerland) · 2026Article
- Drug-drug interactions in targeted cancer therapies: a focus on tyrosine kinase inhibitors.Expert review of clinical pharmacology · 2025Review
- Targeting PTGDS Promotes ferroptosis in peripheral T cell lymphoma through regulating HMOX1-mediated iron metabolism.British journal of cancer · 2025Article
- Relapsed pediatric acute myeloid leukaemia: state-of-the-art in 2023.Haematologica · 2023Review
- Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors.International journal of molecular sciences · 2022Article
- "FLipping" the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors.Cancers · 2022Review
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
purposeTo 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). PATIENTS AND
methodsAfter 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.
resultsThe 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).
conclusionsThe 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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