A phase Ib/II study of ivosidenib with venetoclax +/- azacitidine in IDH1-mutated myeloid malignancies
| Autor: | Curtis A. Lachowiez, Sanam Loghavi, Zhihong Zeng, Tomoyuki Tanaka, Yi June Kim, Hidetaka Uryu, Sven Turkalj, Niels Asger Jakobsen, Marlise R. Luskin, Dzifa Y. Duose, Rebecca S S. Tidwell, Nicholas J. Short, Gautam Borthakur, Tapan M. Kadia, Lucia Masarova, George D. Tippett, Prithviraj Bose, Elias J. Jabbour, Farhad Ravandi, Naval G. Daver, Guillermo Garcia-Manero, Hagop Kantarjian, Jacqueline S. Garcia, Paresh Vyas, Koichi Takahashi, Marina Konopleva, Courtney D. DiNardo |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Blood Cancer Discovery. |
| ISSN: | 2643-3249 2643-3230 |
| DOI: | 10.1158/2643-3230.bcd-22-0205 |
| Popis: | The safety and efficacy of combining the IDH1 inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO+VEN) +/- azacitidine (AZA; IVO+VEN+AZA) was evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n=31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO+VEN+AZA vs. IVO+VEN was 90% vs. 83%. Among MRD-evaluable patients (N=16) 63% attained MRD-negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N=14). Median EFS and OS were 36 (95% CI: 23-NR) and 42 (95% CI: 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked co-occurring mutations, anti-apoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO. |
| Databáze: | OpenAIRE |
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