TY - JOUR
T1 - A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine in IDH1-Mutated Myeloid Malignancies
AU - Lachowiez, Curtis A.
AU - Loghavi, Sanam
AU - Zeng, Zhihong
AU - Tanaka, Tomoyuki
AU - Kim, Yi June
AU - Uryu, Hidetaka
AU - Turkalj, Sven
AU - Jakobsen, Niels Asger
AU - Luskin, Marlise R.
AU - Duose, Dzifa Y.
AU - Tidwell, Rebecca S.S.
AU - Short, Nicholas J.
AU - Borthakur, Gautam
AU - Kadia, Tapan M.
AU - Masarova, Lucia
AU - Tippett, George D.
AU - Bose, Prithviraj
AU - Jabbour, Elias J.
AU - Ravandi, Farhad
AU - Daver, Naval G.
AU - Garcia-Manero, Guillermo
AU - Kantarjian, Hagop
AU - Garcia, Jacqueline S.
AU - Vyas, Paresh
AU - Takahashi, Koichi
AU - Konopleva, Marina
AU - DiNardo, Courtney D.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/7
Y1 - 2023/7
N2 - The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were 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 versus IVO + VEN was 90% versus 83%. Among measurable residual disease (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 event-free survival and overall survival were 36 [94% CI, 23–not reached (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 cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.
AB - The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were 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 versus IVO + VEN was 90% versus 83%. Among measurable residual disease (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 event-free survival and overall survival were 36 [94% CI, 23–not reached (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 cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO.
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U2 - 10.1158/2643-3230.BCD-22-0205
DO - 10.1158/2643-3230.BCD-22-0205
M3 - Article
C2 - 37102976
AN - SCOPUS:85160750427
SN - 2643-3230
VL - 4
SP - 276
EP - 293
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 4
ER -