Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.1276-1276
• Main Authors: Stein, Eytan M., DiNardo, Courtney D., Fathi, Amir T., Mims, Alice S., Savona, Michael R., Stein, Anthony S., Stone, Richard M., Winer, Eric S., Seet, Christopher S., Döhner, Hartmut, Pollyea, Daniel A., McCloskey, James K, Odenike, Olatoyosi, Lowenberg, Bob, Ossenkoppele, Gert J., Patel, Prapti, Roshal, Mikhail, Frattini, Mark G., Lersch, Frederik, Nabhan, Salah, Almon, Caroline, Saatcioglu, Duygu, Zhang, Vickie, Cooper, Michael, Kantarjian, Hagop, Tallman, Martin S.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-146507

Background: Ivosidenib (IVO) and enasidenib (ENA) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, FDA-approved for the treatment of relapsed/refractory IDH-mutant acute myeloid leukemia (AML). Here we report updated response and survival results from a phase 1 study of these agents when combined with intensive chemotherapy in patients with newly diagnosed m IDH1/2 AML. Methods: The design of this open-label, multicenter, phase 1 study (NCT02632708) has been previously described. Briefly, eligible patients with newly diagnosed m IDH1 or m IDH2 AML were treated with induction therapy (daunorubicin 60 mg/m 2/day or idarubicin 12 mg/m 2/day × 3 days with cytarabine 200 mg/m 2/day × 7 days) in combination with either IVO 500 mg once daily (for m IDH1) or ENA 100 mg once daily (for m IDH2). After induction, patients received up to 4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who completed or were ineligible for consolidation continued on maintenance IVO or ENA until the end of the study. IDH mutation clearance and measurable residual disease (MRD) negativity were assessed using BEAMing digital PCR and multiparameter flow cytometry (Stein et al. Blood 2021). Results: As of 16-Jan-2020, 153 patients had been treated: 60 in the IVO cohort (median age 62.5 years, range 24-76) and 93 in the ENA cohort (median age 63.0 years, range 27-77); 2 patients assigned to start ENA on Day 8 had an ongoing adverse event or died on Day 8, and therefore never received ENA and were not included in the efficacy analysis. Secondary AML (sAML; arising after an antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 18/60 (30.0%) IVO-treated patients and in 35/93 (37.6%) ENA-treated patients. In patients with sAML, 4 (22.2%) and 17 (48.6%) IVO-treated and ENA-treated patients, respectively, had previously received a hypomethylating agent. IVO or ENA combined with induction and consolidation were well tolerated (Stein et al . Blood 2021). Among the 60 IVO-treated patients, a response of complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with incomplete platelet recovery (CRp) was achieved in 37/42 (88.1%) patients with de novo AML and in 10/18 (55.6%) patients with sAML. Among the 91 ENA-treated patients, a response of CR, CRi, or CRp was achieved in 45/56 (80.4%) patients with de novo AML and in 22/35 (62.9%) patients with sAML. Best overall response is reporte