Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia

Abstract

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

New directions for emerging therapies in acute myeloid leukemia: the next chapter

“…A phase 1/2 study evaluating single-agent ivosidenib in frontline older and unfit patients with newly diagnosed IDH1 -mutated AML reported an ORR of 42% and CR rate of 30% (ref. 68 ).…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Using mutant isocitrate dehydrogenase as a therapeutic drug target, selecting pan-mutant IDH1/2 inhibitors in clinical trials and other mutant IDH inhibitors are under development [82,83]. In patients with advanced IDH1-mutated R/R AML, ivosidenib demonstrated durable remissions, and molecular remissions in some patients with complete remission [84]. Different IDH inhibitor therapeutic agents are summarized in Table 2 [ [85][86][87][88][89][90].…”

Advances in Acute Myeloid Leukemia: Recently Approved Therapies and Drugs in Development

“…Traditional chemotherapy treatments consist of either a high dose regimen containing cytarabine for 7 days and an anthracycline given for 3 days (7 + 3), or lower-intensity treatments with a hypomethylating agent (HMA) such as azacitidine (AZA) or decitabine, or low dose cytarabine (LDAC) [3]. Mitoxantrone can also be used interchangeably with anthracyclines [4].…”

“…IDH1 and IDH2 are metabolic enzymes that normally catalyze the conversion of isocitrate to α-ketoglutarate, however, mutations in IDH1 and IDH2 encode neo-morphic enzymes that instead reduce α-ketoglutarate to R-2-hydroxyglutarate (2HG), an onco-metabolite that promotes cytokine-independent cell proliferation with blocked differentiation [26,27]. These genetic modifications can also lead to increased epigenetic alterations including histone and DNA methylation which can impair differentiation, as well as other chromatin modifications, altered response to hypoxia, and increased leukemogenic effects by inducing dependence on B-cell lymphoma 2 (BCL-2) [3,28,29] While mutant IDH is associated with poor prognosis in other malignancies, its prognostic value is inconsistently defined in AML, which may be the result of a complex gene-gene interaction [30][31][32]. For instance, IDH2-R140 shows strong co-mutation rate with NPM1, while IDH2-R172 occurs independently of NPM1 and other class-defining lesions [32].…”