TY - JOUR
T1 - Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib
AU - Stein, Eytan M.
AU - DiNardo, Courtney D.
AU - Fathi, Amir T.
AU - Pollyea, Daniel A.
AU - Stone, Richard M.
AU - Altman, Jessica K.
AU - Roboz, Gail J.
AU - Patel, Manish R.
AU - Collins, Robert
AU - Flinn, Ian W.
AU - Sekeres, Mikkael A.
AU - Stein, Anthony S.
AU - Kantarjian, Hagop M.
AU - Levine, Ross L.
AU - Vyas, Paresh
AU - MacBeth, Kyle J.
AU - Tosolini, Alessandra
AU - VanOostendorp, Jason
AU - Xu, Qiang
AU - Gupta, Ira
AU - Lila, Thomas
AU - Risueno, Alberto
AU - Yen, Katharine E.
AU - Wu, Bin
AU - Attar, Eyal C.
AU - Tallman, Martin S.
AU - de Botton, Stéphane
N1 - Funding Information:
This work was supported by Celgene Corporation and Agios Pharmaceuticals, Inc. Statistical support was provided by Nora Tu, formerly of Celgene Corporation. Editorial support was provided by Sheila Truten and Kelly Dittmore (Medical Communication Company, Inc., Wynnewood, PA), funded by Celgene Corporation.
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/2/14
Y1 - 2019/2/14
N2 - Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion–dependent and 53 (40.2%) platelet transfusion–dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.
AB - Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion–dependent and 53 (40.2%) platelet transfusion–dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.
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U2 - 10.1182/blood-2018-08-869008
DO - 10.1182/blood-2018-08-869008
M3 - Article
C2 - 30510081
AN - SCOPUS:85061474021
SN - 0006-4971
VL - 133
SP - 676
EP - 687
JO - Blood
JF - Blood
IS - 7
ER -