Hematologic Improvements With Ivosidenib + Azacitidine Compared to Placebo + Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia

Background

• Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1).
• IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival, and complete remission + partial hematologic recovery rates compared with placebo (PBO) + AZA in patients (pts) with newly diagnosed IDH1-mutant acute myeloid leukemia (AML) in the phase 3 AGILE trial (NCT03173248).

Methods

• Pts were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles (n = 72) or PBO+AZA (n = 74).
• Red blood cell (RBC)/platelet transfusion history were assessed at screening and follow-up.
• Bone marrow (BM) and peripheral blood samples were obtained at screening and during weeks 9, 17, 25, 33, 41, and 53; every 24 weeks thereafter; and at end of treatment and during EFS follow up.
• Samples were analyzed at each local site according to ICSH guidelines.

Results

• In the IVO+AZA and PBO+AZA arms, 4.2% and 5.5% of pts, respectively, received concomitant granulocyte colony-stimulating factor.
• Hemoglobin levels steadily increased from baseline at a similar rate in both treatment arms.
• Mean platelet count recovered from baseline values in the IVO+AZA and PBO+AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population.
• In pts receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ̃2.0 x 109/L).
• Mean neutrophil counts initially declined with PBO+AZA before slowly recovering to near-normal levels after 36-40 weeks.
• The increased blood counts were accompanied by a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks.
• The decline in BM blasts was slower in the PBO+AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively).
• Among patients who were RBC/platelet transfusion-dependent at baseline (̃54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the PBO+AZA arm (1-sided p = 0.0032).
• Additionally, fewer adverse events of febrile neutropenia (28.2% vs 34.2%) and infections (28.2% vs 49.3%) were reported in the IVO+AZA arm compared to the PBO+AZA arm.

Conclusions

• IVO+AZA demonstrated a significant clinical benefit compared with PBO+AZA and this sub-analysis demonstrated a rapidly improved recovery of blood counts and a reduced dependence on RBC and/or platelet transfusion.
• Moreover, rates of febrile neutropenia and infections were reduced with IVO+AZA. Clinical trial information: NCT03173248.

Dohner H, Montesinos P, Polo SV, et al. Hematologic improvements with ivosidenib + azacitidine compared to placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia. Abstract presented at: 2022 American Society of Clinical Oncology, June 3-7, 2022; Chicago, Illinois, and virtual. Abstract 7042.