Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML Journal Article
| Authors: | 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, E.; 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. |
| Article 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.). Copyright © 2018 Massachusetts Medical Society. |
| Keywords: | adolescent; adult; aged; aged, 80 and over; middle aged; survival rate; young adult; genetics; mutation; leukemia, myeloid, acute; clinical trial; mortality; dose response; follow up; follow-up studies; recurrence; hemoglobin; drug resistance; dose-response relationship, drug; drug resistance, neoplasm; enzyme inhibitor; enzyme inhibitors; multicenter study; remission; remission induction; recurrent disease; cell count; phase 1 clinical trial; administration, oral; hemoglobins; oral drug administration; isocitrate dehydrogenase; acute myeloid leukemia; idh1 protein, human; very elderly; humans; human; male; female; antagonists and inhibitors |
| Journal Title: | New England Journal of Medicine |
| Volume: | 378 |
| Issue: | 25 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2018-06-21 |
| Start Page: | 2386 |
| End Page: | 2398 |
| Language: | English |
| DOI: | 10.1056/NEJMoa1716984 |
| PUBMED: | 29860938 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2018 -- Source: Scopus |
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