Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

Eytan M. Stein, Courtney D. DiNardo, Daniel A. Pollyea, Amir T. Fathi, Gail J. Roboz, J. K. Altman, Richard M. Stone, Daniel J. Deangelo, Ross L. Levine, Ian W. Flinn, Hagop M. Kantarjian, Robert Collins, Manish R. Patel, Arthur E. Frankel, Anthony Stein, Mikkael A. Sekeres, Ronan T. Swords, Bruno C. Medeiros, Christophe Willekens, Paresh Vyas & 7 others Alessandra Tosolini, Qiang Xu, Robert D. Knight, Katharine E. Yen, Sam Agresta, Stephane De Botton, Martin S. Tallman

Research output: Contribution to journalArticle

265 Citations (Scopus)

Abstract

Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor–associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.

Original languageEnglish (US)
Pages (from-to)722-731
Number of pages10
JournalBlood
Volume130
Issue number6
DOIs
StatePublished - Aug 10 2017

Fingerprint

Isocitrate Dehydrogenase
Acute Myeloid Leukemia
Refractory materials
Pharmacodynamics
Pharmacokinetics
Maximum Tolerated Dose
Cytotoxicity
Histones
Safety
Granulocyte Precursor Cells
Hyperbilirubinemia
Survival
DNA
Enzymes
Proteins
Mutation
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Stein, E. M., DiNardo, C. D., Pollyea, D. A., Fathi, A. T., Roboz, G. J., Altman, J. K., ... Tallman, M. S. (2017). Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood, 130(6), 722-731. https://doi.org/10.1182/blood-2017-04-779405

Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. / Stein, Eytan M.; DiNardo, Courtney D.; Pollyea, Daniel A.; Fathi, Amir T.; Roboz, Gail J.; Altman, J. K.; Stone, Richard M.; Deangelo, Daniel J.; Levine, Ross L.; Flinn, Ian W.; Kantarjian, Hagop M.; Collins, Robert; Patel, Manish R.; Frankel, Arthur E.; Stein, Anthony; Sekeres, Mikkael A.; Swords, Ronan T.; Medeiros, Bruno C.; Willekens, Christophe; Vyas, Paresh; Tosolini, Alessandra; Xu, Qiang; Knight, Robert D.; Yen, Katharine E.; Agresta, Sam; De Botton, Stephane; Tallman, Martin S.

In: Blood, Vol. 130, No. 6, 10.08.2017, p. 722-731.

Research output: Contribution to journalArticle

Stein, EM, DiNardo, CD, Pollyea, DA, Fathi, AT, Roboz, GJ, Altman, JK, Stone, RM, Deangelo, DJ, Levine, RL, Flinn, IW, Kantarjian, HM, Collins, R, Patel, MR, Frankel, AE, Stein, A, Sekeres, MA, Swords, RT, Medeiros, BC, Willekens, C, Vyas, P, Tosolini, A, Xu, Q, Knight, RD, Yen, KE, Agresta, S, De Botton, S & Tallman, MS 2017, 'Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia', Blood, vol. 130, no. 6, pp. 722-731. https://doi.org/10.1182/blood-2017-04-779405
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017 Aug 10;130(6):722-731. https://doi.org/10.1182/blood-2017-04-779405
Stein, Eytan M. ; DiNardo, Courtney D. ; Pollyea, Daniel A. ; Fathi, Amir T. ; Roboz, Gail J. ; Altman, J. K. ; Stone, Richard M. ; Deangelo, Daniel J. ; Levine, Ross L. ; Flinn, Ian W. ; Kantarjian, Hagop M. ; Collins, Robert ; Patel, Manish R. ; Frankel, Arthur E. ; Stein, Anthony ; Sekeres, Mikkael A. ; Swords, Ronan T. ; Medeiros, Bruno C. ; Willekens, Christophe ; Vyas, Paresh ; Tosolini, Alessandra ; Xu, Qiang ; Knight, Robert D. ; Yen, Katharine E. ; Agresta, Sam ; De Botton, Stephane ; Tallman, Martin S. / Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. In: Blood. 2017 ; Vol. 130, No. 6. pp. 722-731.
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abstract = "Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12{\%} of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12{\%}) and IDH-inhibitor–associated differentiation syndrome (7{\%}). Among patients with relapsed or refractory AML, overall response rate was 40.3{\%}, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3{\%}) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.",
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T1 - Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia

AU - Stein, Eytan M.

AU - DiNardo, Courtney D.

AU - Pollyea, Daniel A.

AU - Fathi, Amir T.

AU - Roboz, Gail J.

AU - Altman, J. K.

AU - Stone, Richard M.

AU - Deangelo, Daniel J.

AU - Levine, Ross L.

AU - Flinn, Ian W.

AU - Kantarjian, Hagop M.

AU - Collins, Robert

AU - Patel, Manish R.

AU - Frankel, Arthur E.

AU - Stein, Anthony

AU - Sekeres, Mikkael A.

AU - Swords, Ronan T.

AU - Medeiros, Bruno C.

AU - Willekens, Christophe

AU - Vyas, Paresh

AU - Tosolini, Alessandra

AU - Xu, Qiang

AU - Knight, Robert D.

AU - Yen, Katharine E.

AU - Agresta, Sam

AU - De Botton, Stephane

AU - Tallman, Martin S.

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N2 - Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor–associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498.

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