Molecular Characterization of Clinical Response and Relapse in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib and Azacitidine

Background: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a disease exhibiting a dynamic mutational landscape over time. Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with AML. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory (R/R) AML and newly diagnosed (ND) AML in adults ≥ 75 years (yrs) of age or with comorbidities precluding intensive induction chemotherapy (IC). In an ongoing phase 1b study (NCT02677922), 23 pts (11 male; median age 76 yrs [range 61-88]) with mIDH1 ND AML received IVO 500 mg daily and subcutaneous azacitidine (AZA) 75 mg/m2 on Days 1-7 in 28-day cycles. As of 19Feb2019, median number of treatment cycles was 15 (range 1-30); 10 pts remained on treatment. Overall response rate (complete remission [CR] + CRi [incomplete neutrophil recovery] + CRp [incomplete platelet recovery] + morphologic leukemia-free state [MLFS]) was 78% (18/23): including CR in 61% (14/23) and CR with partial hematologic recovery (CRh) in 9% (2/23). mIDH1 clearance assessed in bone marrow mononuclear cells (BMMCs) by BEAMing digital PCR (detection limit 0.02-0.04%) was observed in 11/16 pts (69%) with CR/CRh, including 10/14 (71%) with CR. Aim: Characterize clonal evolution and resistance in pts with mIDH1 ND AML treated on study with IVO + AZA. Methods: The secondary efficacy endpoint of CRh was sponsor derived and defined as CR with absolute neutrophil count > 0.5 X 109/L and platelets > 50 X 109/L. Bulk DNA sequencing (DNA-seq, 1400-gene ACE Extended Cancer Panel, 2% variant allele detection limit) was performed on BMMCs and/or peripheral blood mononuclear cells (PBMCs). Single-cell (sc) targeted DNA-seq was performed on PBMCs using a microfluidic platform (Tapestri®) with a 20-gene AML panel capable of detecting rare subclones down to 0.1%. Results: To identify mechanisms of acquired resistance, longitudinal bulk DNA-seq was analyzed for 22/23 pts, including 5 pts with available samples at relapse or disease progression (3 CR and 1 MLFS with morphological relapse; 1 CRh with disease progression). Mutations not detected at baseline but emerging during therapy were categorized into canonical biological pathways (Table). Emerging mutations were observed in 9/22 (41%) pts, including 4 with multiple mutations. 3/22 (14%) pts had emerging IDH2 m