Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
American Society of Hematology
2018
|
| _version_ | 1826283130856669184 |
|---|---|
| author | Stein, EM Dinardo, CD Fathi, AT Pollyea, DA Stone, RM Altman, JK Roboz, GJ Patel, MR Collins, R Flinn, IW Sekeres, MA Stein, AS Kantarjian, HM Levine, RL Vyas, P Macbeth, KJ Tosolini, A Vanoostendorp, J Xu, Q Gupta, I Lila, T Risueno, A Yen, KE Wu, B Attar, EC Tallman, MS De Botton, S |
| author_facet | Stein, EM Dinardo, CD Fathi, AT Pollyea, DA Stone, RM Altman, JK Roboz, GJ Patel, MR Collins, R Flinn, IW Sekeres, MA Stein, AS Kantarjian, HM Levine, RL Vyas, P Macbeth, KJ Tosolini, A Vanoostendorp, J Xu, Q Gupta, I Lila, T Risueno, A Yen, KE Wu, B Attar, EC Tallman, MS De Botton, S |
| author_sort | Stein, EM |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T00:54:18Z |
| format | Journal article |
| id | oxford-uuid:877f3a5e-79cb-4fe0-abef-2d54390b5d1a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:54:18Z |
| publishDate | 2018 |
| publisher | American Society of Hematology |
| record_format | dspace |
| spelling | oxford-uuid:877f3a5e-79cb-4fe0-abef-2d54390b5d1a2022-03-26T22:11:06ZMolecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenibJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:877f3a5e-79cb-4fe0-abef-2d54390b5d1aEnglishSymplectic Elements at OxfordAmerican Society of Hematology2018Stein, EMDinardo, CDFathi, ATPollyea, DAStone, RMAltman, JKRoboz, GJPatel, MRCollins, RFlinn, IWSekeres, MAStein, ASKantarjian, HMLevine, RLVyas, PMacbeth, KJTosolini, AVanoostendorp, JXu, QGupta, ILila, TRisueno, AYen, KEWu, BAttar, ECTallman, MSDe Botton, SApproximately 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. |
| spellingShingle | Stein, EM Dinardo, CD Fathi, AT Pollyea, DA Stone, RM Altman, JK Roboz, GJ Patel, MR Collins, R Flinn, IW Sekeres, MA Stein, AS Kantarjian, HM Levine, RL Vyas, P Macbeth, KJ Tosolini, A Vanoostendorp, J Xu, Q Gupta, I Lila, T Risueno, A Yen, KE Wu, B Attar, EC Tallman, MS De Botton, S Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| title | Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| title_full | Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| title_fullStr | Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| title_full_unstemmed | Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| title_short | Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| title_sort | molecular remission and response patterns in patients with mutant idh2 acute myeloid leukemia treated with enasidenib |
| work_keys_str_mv | AT steinem molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT dinardocd molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT fathiat molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT pollyeada molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT stonerm molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT altmanjk molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT robozgj molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT patelmr molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT collinsr molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT flinniw molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT sekeresma molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT steinas molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT kantarjianhm molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT levinerl molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT vyasp molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT macbethkj molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT tosolinia molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT vanoostendorpj molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT xuq molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT guptai molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT lilat molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT risuenoa molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT yenke molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT wub molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT attarec molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT tallmanms molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib AT debottons molecularremissionandresponsepatternsinpatientswithmutantidh2acutemyeloidleukemiatreatedwithenasidenib |