Abstract 1339: Investigations into rational combination approaches with ivosidenib in a mutant IDH1 acute myeloid leukemia patient-derived xenograft model

Autor: Brandon Nicolay, Chris Bowden, Christine C. Hudson, Rohini Narayanaswamy, Sebastien Ronseaux
Rok vydání: 2021
Předmět:
Zdroj: Cancer Research. 81:1339-1339
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.am2021-1339
Popis: Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) arise in roughly 6-10% of patients with acute myeloid leukemia (AML). These mutations lead to the production of the oncometabolite 2-hydroxyglutarate at concentrations shown to interfere with epigenetic control of gene expression, which prevents hematopoietic cell maturation. Ivosidenib (IVO; AG-120) is an oral, potent, targeted oral inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory AML patients and mIDH1 newly diagnosed (ND) AML in adults ≥ 75 years of age or with comorbidities precluding intensive induction chemotherapy. Methods: Currently, IVO is being investigated in combination with azacitidine (AZA) in the actively enrolling phase 3 AGILE study (NCT03173248). To support this ongoing effort, studies were undertaken to explore the IVO + AZA combination in a mIDH1 AML patient-derived xenograft (PDX) model in vivo. These studies examined the timing of IVO + AZA treatment with respect to disease burden control and durability in mice inoculated with a disseminated mIDH1 AML PDX model, both as a frontline treatment as well as in a maintenance therapy setting following either venetoclax (VEN) + AZA, or VEN + AZA + IVO. In addition, the studies examined the utility of combining IVO + VEN as an alternative frontline treatment approach in the same preclinical mIDH1 AML PDX disseminated model. Results: The IVO + AZA combination led to a > 99% reduction in hCD45+ cells within the bone marrow and undetectable disease in the peripheral blood of 7/10 mice by Week 10. Similar results were observed with IVO + VEN treated animal bone marrow (99% reduction in hCD45+ cells) and undetectable disease was observed in 8/10 mice by week 10. Conclusions: Each combination was well tolerated by the mice. The observed disease control with either combination in the animals was greater than any of the three single agents alone. Ongoing follow-up xenograft studies investigating the utility of the combinations with IVO as a maintenance therapy are still ongoing and outcomes will be presented. Citation Format: Christine Hudson, Rohini Narayanaswamy, Sebastien Ronseaux, Chris Bowden, Brandon Nicolay. Investigations into rational combination approaches with ivosidenib in a mutant IDH1 acute myeloid leukemia patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1339.
Databáze: OpenAIRE
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