-Author name in bold denotes the presenting author
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Clinically Relevant Abstract denotes an abstract that is clinically relevant.

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560 Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation Is Safe, Effective, and Leads to MRD-Negative Complete RemissionsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Targeted Therapy
Hematology Disease Topics & Pathways:
Diseases, Adult, AML, Non-Biological, Therapies, chemotherapy, Study Population, Clinically relevant, Myeloid Malignancies
Monday, December 3, 2018: 7:15 AM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

Eytan M. Stein, MD1, Courtney D. DiNardo, MD, MSc2, Amir T. Fathi, MD3, Alice S. Mims, MD4, Keith W. Pratz, MD5, Michael R. Savona, MD6, Anthony S. Stein, MD7, Richard M. Stone, MD8*, Eric S. Winer, MD8, Christopher S. Seet, MD9, Hartmut Döhner, MD10, Daniel A Pollyea, MD11, James K McCloskey, MD12, Olatoyosi Odenike, MD13, Bob Löwenberg, MD, PhD14, Gert J. Ossenkoppele, MD, PhD15, Prapti A. Patel, MD16, Mikhail Roshal, MD, PhD1, Frederik Lersch, RN17*, Salah Nabhan, MS18*, Sung Choe, PhD18*, Hongfang Wang, PhD18*, Lei Hua, PhD18*, Caroline Almon, MS18*, Michael Cooper, MD18 and Martin S. Tallman, MD1

1Memorial Sloan Kettering Cancer Center, New York, NY
2University of Texas MD Anderson Cancer Center, Houston, TX
3Massachusetts General Hospital Cancer Center, Boston, MA
4Comprehensive Cancer Center, The Ohio State University, Columbus, OH
5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
6Vanderbilt-Ingram Center, VUMC, Nashville, TN
7City of Hope Medical Center, Duarte, CA
8Dana-Farber Cancer Institute, Boston, MA
9UCLA Medical Center, Los Angeles, CA
10Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
11University of Colorado School of Medicine, Aurora, CO
12John Thuerer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
13University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL
14Erasmus University Medical Centre, Rotterdam, Netherlands
15VUMC Cancer Center, Amsterdam, Netherlands
16University of Texas Southwestern Medical Center, Dallas, TX
17Celgene International, Boudry, Switzerland
18Agios Pharmaceuticals, Inc., Cambridge, MA

BACKGROUND: Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, approved for the treatment of relapsed/refractory IDH-mutant acute myeloid leukemia (AML). Here we report updated results from a phase 1 study on the safety and efficacy of each of these agents when combined with intensive chemotherapy in patients with newly diagnosed AML, as well as data regarding the rate of measurable residual disease (MRD)-negative complete remissions (CRs), mutation clearance and molecular profiling.

METHODS: In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with induction therapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib until the end of study. For patients who proceed to allogeneic hematopoietic stem cell transplant (HSCT), mIDH inhibitor treatment is discontinued prior to transplant and is not resumed post-transplant.

mIDH1/2 variant allele frequency (VAF) is assessed in bone marrow mononuclear cells using Digital PCR Technology (Sysmex-Inostics Inc). IDH1/2 mutation clearance (IDH-MC) is defined as a reduction in the mIDH1/2 VAF to a level below the limit of detection of this assay (0.02–0.04%) for ≥1 on-treatment time point on or after Day 28 of induction. MRD in bone marrow aspirates is analyzed using multi-parameter flow cytometry. Baseline co-occurring mutations are identified with a 95-gene next generation sequencing panel targeted to hematologic malignancies.

RESULTS: As of May 1, 2018, 134 patients had been treated: 47 with ivosidenib (median age 63 years, range 24–76) and 87 with enasidenib (median age 63 years, range 27–77; Table 1). Secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 33/87 (38%) patients with mIDH2 and in 16/47 (34%) patients with mIDH1. The most frequent co-occurring baseline mutations were DNMT3A, NPM1 and NRAS for patients with IDH1 mutations; and DNMT3A, SRSF2 and ASXL1 for patients with IDH2 mutations.

Ivosidenib or enasidenib combined with induction and consolidation was well tolerated, based on the frequency of grade ≥3 non-hematologic adverse events (Table 2) and hematologic recovery (Table 3). Times for ANC and platelet count recovery were nominally longer in patients with sAML.

Among the 41 ivosidenib-treated patients evaluable for efficacy, a response of CR, CRi or CRp was achieved in 26/28 (93%) patients with de novo AML and 6/13 (46%) patients with sAML (Table 4). Twenty-one patients received ≥1 cycle of consolidation therapy and 11 patients received maintenance after consolidation. Seventeen patients proceeded to HSCT.

Among the 77 enasidenib-treated patients evaluable for efficacy, a response of CR, CRi, or CRp was achieved in 33/45 (73%) patients with de novo AML and in 20/32 (63%) patients with sAML (Table 4). Thirty-seven patients received ≥1 cycle of consolidation therapy, 6 patients received maintenance directly after induction and 11 patients received maintenance after consolidation. Thirty-three patients proceeded to HSCT.

Longitudinal VAF data are available for 31 ivosidenib-treated patients and 60 enasidenib-treated patients. In patients who achieved a CR, IDH-MC was observed in 41% (9/22) of those with mIDH1 (Table 5) and in 30% (11/37) of those with mIDH2 (Table 6). Flow cytometry assessments are available for 21 patients achieving a CR: MRD-negative CRs were observed in 89% (8/9) of those with mIDH1 and in 58% (7/12) of those with mIDH2.

CONCLUSION: Ivosidenib or enasidenib in combination with induction and consolidation therapy has an acceptable safety profile with robust remission rates, MRD-negative CRs, and mutation clearance in a population of older, high-risk patients with mIDH AML. The clinical benefit of adding ivosidenib or enasidenib to induction, consolidation and maintenance therapy for patients with newly diagnosed mIDH AML will be further evaluated in a randomized phase 3 trial.

Disclosures: Stein: Bayer: Consultancy; Agios: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy. DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Fathi: Jazz: Honoraria; Daiichi Sankyo: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Medimmune: Consultancy; Exelexis: Research Funding. Mims: Novartis: Consultancy; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pratz: AbbVie: Consultancy, Research Funding; Agios: Research Funding; Millenium/Takeda: Research Funding; Boston Scientific: Consultancy; Astellas: Consultancy, Research Funding. Savona: Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein: Celgene: Speakers Bureau; Amgen: Speakers Bureau. Stone: Astellas: Consultancy; Ono: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Orsenix: Consultancy; Merck: Consultancy; Cornerstone: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Fujifilm: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Pfizer: Consultancy; Sumitomo: Consultancy. Döhner: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding. Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. McCloskey: Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership; Amgen Pharmaceuticals: Speakers Bureau; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Pfizer: Consultancy; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; COTA: Equity Ownership; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; COTA: Equity Ownership; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Pfizer: Consultancy. Odenike: ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Löwenberg: Clear Creek Bio Ltd: Consultancy, Honoraria; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board “International Journal of Hematology”: Membership on an entity's Board of Directors or advisory committees; Editorial Board “The Netherlands Journal of Medicine”: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; “Up-to-Date”, section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Editorial Board “European Oncology & Haematology”: Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ossenkoppele: Roche: Consultancy, Honoraria; Karyopharm: Consultancy, Research Funding; Genmab: Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding. Patel: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; France Foundation: Honoraria; Dava Oncology: Honoraria. Lersch: Celgene: Employment. Nabhan: Agios: Employment. Choe: Agios: Employment, Equity Ownership. Wang: Agios: Employment, Equity Ownership. Hua: Agios: Employment, Equity Ownership. Almon: Agios: Employment, Equity Ownership. Cooper: Agios: Employment, Equity Ownership. Tallman: BioSight: Other: Advisory board; AbbVie: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding.

*signifies non-member of ASH