Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial
Abstract Background Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial o...
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BMC
2025-01-01
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| Series: | Journal of Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s13045-024-01657-z |
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| author | Jorge E. Cortes Gail J. Roboz Maria R. Baer Brian A. Jonas Gary J. Schiller Karen Yee P. Brent Ferrell Jay Yang Eunice S. Wang William G. Blum Alice Mims Hua Tian Aaron Sheppard Stéphane de Botton Pau Montesinos Antonio Curti Justin M. Watts the Olutasidenib Combination Therapy Study Group |
| author_facet | Jorge E. Cortes Gail J. Roboz Maria R. Baer Brian A. Jonas Gary J. Schiller Karen Yee P. Brent Ferrell Jay Yang Eunice S. Wang William G. Blum Alice Mims Hua Tian Aaron Sheppard Stéphane de Botton Pau Montesinos Antonio Curti Justin M. Watts the Olutasidenib Combination Therapy Study Group |
| author_sort | Jorge E. Cortes |
| collection | DOAJ |
| description | Abstract Background Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Methods Adult patients with mIDH1 R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Results Sixty-seven patients with R/R mIDH1 R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event. Conclusions Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy. Trial registration NCT02719574. |
| format | Article |
| id | doaj-art-6720460994e14f329f75be03443f0054 |
| institution | Kabale University |
| issn | 1756-8722 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj-art-6720460994e14f329f75be03443f00542025-01-19T12:36:22ZengBMCJournal of Hematology & Oncology1756-87222025-01-0118111310.1186/s13045-024-01657-zOlutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trialJorge E. Cortes0Gail J. Roboz1Maria R. Baer2Brian A. Jonas3Gary J. Schiller4Karen Yee5P. Brent Ferrell6Jay Yang7Eunice S. Wang8William G. Blum9Alice Mims10Hua Tian11Aaron Sheppard12Stéphane de Botton13Pau Montesinos14Antonio Curti15Justin M. Watts16the Olutasidenib Combination Therapy Study GroupGeorgia Cancer Center at Augusta UniversityCornell University Weill Medical CollegeGreenebaum Comprehensive Cancer Center, University of MarylandDavis Comprehensive Cancer Center, University of CaliforniaRonald Reagan UCLA Medical CenterPrincess Margaret Cancer CentreVanderbilt University Medical CenterKarmanos Cancer InstituteRoswell Park Cancer InstituteEmory Winship Cancer InstituteThe Ohio State UniversityRigel Pharmaceuticals, Inc.Rigel Pharmaceuticals, Inc.Hematologie Clinique, Institut Gustave RoussyPM-Hematology Department, Hospital Universitari I Politècnic La FeInstitute of Hematology, IRCCS Azienda Ospedaliero-Universitaria Di BolognaSylvester Comprehensive Cancer Center, University of MiamiAbstract Background Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy. Methods Adult patients with mIDH1 R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety. Results Sixty-seven patients with R/R mIDH1 R132 AML received combination OLU + AZA. Median age was 66 years (range 28–82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21–44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17–39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38–63) patients. Median overall survival was 12.9 months (95% CI 18.7–19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24–52) patients, CR was achieved in 16/51 (31%; 95% CI 19–46), and overall response was achieved in 30/51 (59%; 95% CI 44–72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event. Conclusions Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy. Trial registration NCT02719574.https://doi.org/10.1186/s13045-024-01657-zIsocitrate dehydrogenase-1Hypomethylating agentMutant IDH1 inhibitorRelapsedRefractoryAML |
| spellingShingle | Jorge E. Cortes Gail J. Roboz Maria R. Baer Brian A. Jonas Gary J. Schiller Karen Yee P. Brent Ferrell Jay Yang Eunice S. Wang William G. Blum Alice Mims Hua Tian Aaron Sheppard Stéphane de Botton Pau Montesinos Antonio Curti Justin M. Watts the Olutasidenib Combination Therapy Study Group Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial Journal of Hematology & Oncology Isocitrate dehydrogenase-1 Hypomethylating agent Mutant IDH1 inhibitor Relapsed Refractory AML |
| title | Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial |
| title_full | Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial |
| title_fullStr | Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial |
| title_full_unstemmed | Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial |
| title_short | Olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory mIDH1 acute myeloid leukemia: a multicohort open-label phase 1/2 trial |
| title_sort | olutasidenib in combination with azacitidine induces durable complete remissions in patients with relapsed or refractory midh1 acute myeloid leukemia a multicohort open label phase 1 2 trial |
| topic | Isocitrate dehydrogenase-1 Hypomethylating agent Mutant IDH1 inhibitor Relapsed Refractory AML |
| url | https://doi.org/10.1186/s13045-024-01657-z |
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