AG-221 offers a survival advantage in a primary human IDH2 mutant AML xenograft model

Yen, Katherine; Wang, F.; Travins, Jeremy; Chen, Y.; Yang, Hua; Straley, Kim; Choe, Sung; Dorsch, Marion; Agresta, Samuel V.; Schenkein, David P.; Biller, Scott A.; Su, Michael

doi:10.1093/annonc/mdv089.2

Cited by 7 publications

(12 citation statements)

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“…2-HG suppression in patients with R172 mIDH2 was less than in patients with R140 mIDH2 rrAML (median suppression of 70.9% and 94.9%, respectively [P , .001]), consistent with preclinical data and an interim analysis of samples from study AG-221-C-001 ( Figure 1A). [14][15][16][22][23][24] Of note, 5 patients during treatment had an increase in 2-HG. Two of these patients achieved a best response of PR despite never having 2-HG levels below baseline in multiple samples analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…18 Additionally, our data confirm the preclinical mechanism of action of mIDH2 inhibition by enasidenib and provide the first insight into the genetic basis of primary resistance. 10,[14][15][16] Evidence suggests that human AML comprises a hierarchy of both tumor-propagating leukemic stem cells (LSCs) arrested at a progenitor or precursor stage of hemopoiesis and more mature nontumor propagating leukemic cells. 30,31 Our observations demonstrate that enasidenib promotes terminal differentiation of mIDH2 leukemic cells of granulocytic lineage in patients who achieve CR or PR.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] In preclinical studies, enasidenib (AG-221/CC-90007), a small-molecule inhibitor of mIDH2, reduced serum 2-HG, DNA hypermethylation, and repressive histone marks and promoted hematopoietic differentiation in R140 and R172 mIDH2 models. [14][15][16][17] In a phase 1/2 clinical trial, enasidenib demonstrated clinical activity in patients with both R140 and R172 mIDH2 relapsed/refractory AML (rrAML) with an overall response rate (ORR) of 40.3%. 18 Here, we analyzed samples from this study to elucidate the mechanisms of action of enasidenib in R140 and R172 mIDH2 rrAML patients and to identify response biomarkers to targeted mIDH2 therapy.…”

Section: Introductionmentioning

confidence: 99%

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Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

Amatangelo¹,

Quek

Shih

et al. 2017

Blood

316

307

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• Enasidenib inhibits mIDH2, leading to leukemic cell differentiation with emergence of functional mIDH2 neutrophils in rrAML patients.• RAS pathway mutations and increased mutational burden overall are associated with a decreased response rate to mIDH2 inhibition.Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ∼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies. (Blood. 2017;130(6):732-741)

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response

Amatangelo¹,

Quek

Shih

et al. 2017

Blood

316

307

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“…Recently, the IDH1 inhibitor AGI-14100 was tested in combination with Ara-C in a xenograft model, which resulted in a stronger decrease of bone marrow tumor burden than either treatment alone [92]. Specific inhibitors for IDH2 R140 have also been developed; AGI-6780 [94] and AG-221 [95]. Both compounds reduce 2HG production and induce cellular differentiation.…”

Section: Possibilities For Treatmentmentioning

confidence: 99%

5-Hydroxymethylcytosine: An epigenetic mark frequently deregulated in cancer

Kroeze

Reijden

Jansen

2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…128 The IDH2 inhibitor AG-221 decreased 2-HG levels by >90%, induced differentiation and prolonged survival in a dose- dependent manner in an AML IDH2R140Q xenograft model. 129 Preliminary results of its first-in-human phase I/II dose escalation study (NCT01915498) in patients with advanced myeloid malignancies showed CR and PR rates of 18% and 15%, respectively, in 128 relapsed/refractory AML patients, irrespective of the number of prior treatment regimens. The median duration of response was 6 months.…”

Section: Idh Inhibitorsmentioning

confidence: 99%