Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML

C. D. DiNardo, E. M. Stein, S. De Botton, G. J. Roboz, J. K. Altman, A. S. Mims, R. Swords, R. H. Collins, G. N. Mannis, D. A. Pollyea, W. Donnellan, A. T. Fathi, A. Pigneux, H. P. Erba, G. T. Prince, A. S. Stein, G. L. Uy, J. M. Foran, Elie Traer, R. K. Stuart & 20 others M. L. Arellano, J. L. Slack, M. A. Sekeres, C. Willekens, S. Choe, H. Wang, V. Zhang, K. E. Yen, S. M. Kapsalis, H. Yang, D. Dai, B. Fan, M. Goldwasser, H. Liu, S. Agresta, B. Wu, E. C. Attar, M. S. Tallman, R. M. Stone, H. M. Kantarjian

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

BACKGROUND Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting cooccurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839.).

Original languageEnglish (US)
Pages (from-to)2386-2398
Number of pages13
JournalNew England Journal of Medicine
Volume378
Issue number25
DOIs
StatePublished - Jun 21 2018

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Isocitrate Dehydrogenase
Acute Myeloid Leukemia
Confidence Intervals
Mutation
Safety
Febrile Neutropenia
Leukocytosis
Platelet Count
Thrombocytopenia
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

DiNardo, C. D., Stein, E. M., De Botton, S., Roboz, G. J., Altman, J. K., Mims, A. S., ... Kantarjian, H. M. (2018). Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. New England Journal of Medicine, 378(25), 2386-2398. https://doi.org/10.1056/NEJMoa1716984

Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. / DiNardo, C. D.; Stein, E. M.; De Botton, S.; Roboz, G. J.; Altman, J. K.; Mims, A. S.; Swords, R.; Collins, R. H.; Mannis, G. N.; Pollyea, D. A.; Donnellan, W.; Fathi, A. T.; Pigneux, A.; Erba, H. P.; Prince, G. T.; Stein, A. S.; Uy, G. L.; Foran, J. M.; Traer, Elie; Stuart, R. K.; Arellano, M. L.; Slack, J. L.; Sekeres, M. A.; Willekens, C.; Choe, S.; Wang, H.; Zhang, V.; Yen, K. E.; Kapsalis, S. M.; Yang, H.; Dai, D.; Fan, B.; Goldwasser, M.; Liu, H.; Agresta, S.; Wu, B.; Attar, E. C.; Tallman, M. S.; Stone, R. M.; Kantarjian, H. M.

In: New England Journal of Medicine, Vol. 378, No. 25, 21.06.2018, p. 2386-2398.

Research output: Contribution to journalArticle

DiNardo, CD, Stein, EM, De Botton, S, Roboz, GJ, Altman, JK, Mims, AS, Swords, R, Collins, RH, Mannis, GN, Pollyea, DA, Donnellan, W, Fathi, AT, Pigneux, A, Erba, HP, Prince, GT, Stein, AS, Uy, GL, Foran, JM, Traer, E, Stuart, RK, Arellano, ML, Slack, JL, Sekeres, MA, Willekens, C, Choe, S, Wang, H, Zhang, V, Yen, KE, Kapsalis, SM, Yang, H, Dai, D, Fan, B, Goldwasser, M, Liu, H, Agresta, S, Wu, B, Attar, EC, Tallman, MS, Stone, RM & Kantarjian, HM 2018, 'Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML', New England Journal of Medicine, vol. 378, no. 25, pp. 2386-2398. https://doi.org/10.1056/NEJMoa1716984
DiNardo CD, Stein EM, De Botton S, Roboz GJ, Altman JK, Mims AS et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. New England Journal of Medicine. 2018 Jun 21;378(25):2386-2398. https://doi.org/10.1056/NEJMoa1716984
DiNardo, C. D. ; Stein, E. M. ; De Botton, S. ; Roboz, G. J. ; Altman, J. K. ; Mims, A. S. ; Swords, R. ; Collins, R. H. ; Mannis, G. N. ; Pollyea, D. A. ; Donnellan, W. ; Fathi, A. T. ; Pigneux, A. ; Erba, H. P. ; Prince, G. T. ; Stein, A. S. ; Uy, G. L. ; Foran, J. M. ; Traer, Elie ; Stuart, R. K. ; Arellano, M. L. ; Slack, J. L. ; Sekeres, M. A. ; Willekens, C. ; Choe, S. ; Wang, H. ; Zhang, V. ; Yen, K. E. ; Kapsalis, S. M. ; Yang, H. ; Dai, D. ; Fan, B. ; Goldwasser, M. ; Liu, H. ; Agresta, S. ; Wu, B. ; Attar, E. C. ; Tallman, M. S. ; Stone, R. M. ; Kantarjian, H. M. / Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 25. pp. 2386-2398.
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title = "Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML",
abstract = "BACKGROUND Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10{\%} of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8{\%} of the patients), the IDH differentiation syndrome (in 3.9{\%}), anemia (in 2.2{\%}), thrombocytopenia or a decrease in the platelet count (in 3.4{\%}), and leukocytosis (in 1.7{\%}). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4{\%} (95{\%} confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6{\%} (95{\%} CI, 14.7 to 29.8), and the overall response rate was 41.6{\%} (95{\%} CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95{\%} CI, 5.5 to 12.0), 9.3 months (95{\%} CI, 5.6 to 18.3), and 6.5 months (95{\%} CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35{\%}), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21{\%}) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting cooccurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839.).",
author = "DiNardo, {C. D.} and Stein, {E. M.} and {De Botton}, S. and Roboz, {G. J.} and Altman, {J. K.} and Mims, {A. S.} and R. Swords and Collins, {R. H.} and Mannis, {G. N.} and Pollyea, {D. A.} and W. Donnellan and Fathi, {A. T.} and A. Pigneux and Erba, {H. P.} and Prince, {G. T.} and Stein, {A. S.} and Uy, {G. L.} and Foran, {J. M.} and Elie Traer and Stuart, {R. K.} and Arellano, {M. L.} and Slack, {J. L.} and Sekeres, {M. A.} and C. Willekens and S. Choe and H. Wang and V. Zhang and Yen, {K. E.} and Kapsalis, {S. M.} and H. Yang and D. Dai and B. Fan and M. Goldwasser and H. Liu and S. Agresta and B. Wu and Attar, {E. C.} and Tallman, {M. S.} and Stone, {R. M.} and Kantarjian, {H. M.}",
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TY - JOUR

T1 - Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML

AU - DiNardo, C. D.

AU - Stein, E. M.

AU - De Botton, S.

AU - Roboz, G. J.

AU - Altman, J. K.

AU - Mims, A. S.

AU - Swords, R.

AU - Collins, R. H.

AU - Mannis, G. N.

AU - Pollyea, D. A.

AU - Donnellan, W.

AU - Fathi, A. T.

AU - Pigneux, A.

AU - Erba, H. P.

AU - Prince, G. T.

AU - Stein, A. S.

AU - Uy, G. L.

AU - Foran, J. M.

AU - Traer, Elie

AU - Stuart, R. K.

AU - Arellano, M. L.

AU - Slack, J. L.

AU - Sekeres, M. A.

AU - Willekens, C.

AU - Choe, S.

AU - Wang, H.

AU - Zhang, V.

AU - Yen, K. E.

AU - Kapsalis, S. M.

AU - Yang, H.

AU - Dai, D.

AU - Fan, B.

AU - Goldwasser, M.

AU - Liu, H.

AU - Agresta, S.

AU - Wu, B.

AU - Attar, E. C.

AU - Tallman, M. S.

AU - Stone, R. M.

AU - Kantarjian, H. M.

PY - 2018/6/21

Y1 - 2018/6/21

N2 - BACKGROUND Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting cooccurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839.).

AB - BACKGROUND Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting cooccurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839.).

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