TY - JOUR
T1 - AML-348 A Phase Ib/II Study of Ivosidenib With Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies
AU - Lachowiez, Curtis
AU - Borthakur, Gautam
AU - Loghavi, Sanam
AU - Zeng, Zhihong
AU - Kadia, Tapan
AU - Masarova, Lucia
AU - Takahashi, Koichi
AU - Tippett, George
AU - Garcia, Jacqueline
AU - Bose, Prithviraj
AU - Jabbour, Elias
AU - Ravandi, Farhad
AU - Daver, Naval
AU - Manero, Guillermo Garcia
AU - Vyas, Paresh
AU - Kantarjian, Hagop
AU - Konopleva, Marina
AU - DiNardo, Courtney
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/10
Y1 - 2022/10
N2 - Context: IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1–14), with or without azacitidine (AZA; 75 mg/m2 D1–7) every 28 days. Objectives: Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS). Design: A dose-escalation/-de-escalation study evaluating cohorts of 6 patients enrolled within 4 dose levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Participants: Eligible patients were ≥ age 18 with IDH1+ MDS, newly diagnosed (ND) or relapsed/refractory (R/R) AML. Results: Thirty-one patients enrolled with a median follow-up of 26 months. The median age was 67 years (range: 44–84), 71% had AML (ND: N=14, R/R: N=8), and 29% had MDS. ELN risk was intermediate or adverse in 19% and 55%, respectively (N=17). The ORR was 94% (DL1: 67%, DL2–DL4: 100%); composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). Of the AML patients, 60% attained measurable residual disease–negative CRc by multiparameter flow cytometry. IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%–0.25%) occurred in 64% of patients following cycle 5. Grade 3–5 adverse events (AEs) in ≥ 10% of patients included febrile neutropenia (29%) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in 2 (dose-limiting toxicity in 1), and differentiation syndrome in 4 (G2: N=2, G3: N=2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months, respectively, and 24-month OS was 71% (95% CI: 55–91; ND-AML: 67%, R/R-AML: 50%, MDS: 100%). MRD-negative CRc improved OS (median NR vs. 8 months, P: 0.002) in ND- and R/R-AML. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN±AZA is an effective treatment for IDH1+ myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented.
AB - Context: IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1–14), with or without azacitidine (AZA; 75 mg/m2 D1–7) every 28 days. Objectives: Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS). Design: A dose-escalation/-de-escalation study evaluating cohorts of 6 patients enrolled within 4 dose levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Participants: Eligible patients were ≥ age 18 with IDH1+ MDS, newly diagnosed (ND) or relapsed/refractory (R/R) AML. Results: Thirty-one patients enrolled with a median follow-up of 26 months. The median age was 67 years (range: 44–84), 71% had AML (ND: N=14, R/R: N=8), and 29% had MDS. ELN risk was intermediate or adverse in 19% and 55%, respectively (N=17). The ORR was 94% (DL1: 67%, DL2–DL4: 100%); composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). Of the AML patients, 60% attained measurable residual disease–negative CRc by multiparameter flow cytometry. IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%–0.25%) occurred in 64% of patients following cycle 5. Grade 3–5 adverse events (AEs) in ≥ 10% of patients included febrile neutropenia (29%) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in 2 (dose-limiting toxicity in 1), and differentiation syndrome in 4 (G2: N=2, G3: N=2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months, respectively, and 24-month OS was 71% (95% CI: 55–91; ND-AML: 67%, R/R-AML: 50%, MDS: 100%). MRD-negative CRc improved OS (median NR vs. 8 months, P: 0.002) in ND- and R/R-AML. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN±AZA is an effective treatment for IDH1+ myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented.
KW - AML
KW - IDH1
KW - Phase I/II
KW - ivosidenib
KW - targeted-therapy
KW - venetoclax
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U2 - 10.1016/S2152-2650(22)01276-9
DO - 10.1016/S2152-2650(22)01276-9
M3 - Article
AN - SCOPUS:85138218593
SN - 2152-2650
VL - 22
SP - S240-S241
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
ER -