Phase I Trial Shows Activity of Single-Agent Ivosidenib in IDH1-Mutated AML

Ivosidenib was safe and associated with remissions, transfusion independence, and molecular remissions in patients with relapsed or refractory IDH1-mutated acute myeloid leukemia (AML), according to results from a phase I trial published in the New England Journal of Medicine.

In July 2018, the U.S. Food and Drug Administration approved the small-molecule IDH1 inhibitor for this indication, based on earlier results from this ongoing phase I trial that were presented at the 2017 American Society of Hematology (ASH) Annual Meeting.

“The approval of ivosidenib is profoundly meaningful for the 6 to 10 percent of patients with AML and IDH1 mutations – most of whom are older and not candidates for standard intensive therapy,” lead author Courtney D. DiNardo, MD, from University of Texas MD Anderson Cancer Center, told ASH Clinical News. “We now have a well-tolerated and effective oral and outpatient therapy for them.”

The multicenter, open-label, doseescalation and dose-expansion trial enrolled 258 adult patients (median age = 68 years; range = 18-89 years) with an Eastern Cooperative Oncology Group performance status score ≤2 and a clinically confirmed IDH1 mutation.

All participants received ivosidenib in 28-day cycles, at doses ranging from 100 mg twice-daily to 1,200 mg once-daily. Safety and efficacy were assessed in 179 patients who received ivosidenib 500 mg/day; the primary efficacy population included the 125 patients who had at least six months of follow-up data available. This group included patients with disease that was in second or later relapse, that relapsed following hematopoietic cell transplantation, that was refractory to induction or re-induction chemotherapy, or had relapsed within 12 months after initial therapy.

Nearly all patients (n=177; 98.9%) experienced an adverse event (AE), the most common of which were diarrhea (30.7%), leukocytosis (29.6%), febrile neutropenia (28.5%), nausea (27.9%), and fatigue (25.7%).

Incidence of the “AEs of special interest,” including prolonged QT interval, leukocytosis, and IDH differentiation syndrome are presented in the TABLE.

IDH differentiation syndrome was observed in 19 patients (10.6%), with a median time to onset of 29 days (range = 5-59 days). “Of these 19 patients, seven (37%) also had leukocytosis (grade 2 or 3),” the investigators reported. However, “no events of the IDH differentiation syndrome were of grade 4 or were fatal, and no patients permanently discontinued ivosidenib owing to this toxic effect.”

IDH differentiation syndrome resolved in 17 of 19 patients after administration of glucocorticoids, diuretics, or hydroxyurea.

“Overall, continuous daily oral therapy with ivosidenib was not associated with dose-limiting toxic effects, with the majority of observed AEs expected for a population of immunosuppressed patients with advanced disease,” the authors wrote.

At a median follow-up of 14.8 months (range = 0.2-30.3 months) in the primary efficacy population, the median overall survival was 8.8 months (range = 6.7-10.2 months).

Twenty-nine of the 84 patients (35%) who were dependent on red-cell and/or platelet transfusion at baseline became transfusion independent for a period of 56 days or more after treatment with singleagent ivosidenib.

The overall response rate was 41.6 percent (n=52), which included a complete remission rate of 21.6 percent (n=27) and a complete response (CR)/CR with partial hematologic recovery (CRh) of 30.4 percent (n=38). Patients remained in CR for a median of 9.3 months (range = 5.6-18.3 months) and in CR/CRh for a median of 8.2 months (range = 5.5 to 12.0 months). The investigators also noted that 50.1 percent of participants with CR/CRh were alive at 18-month follow-up.

In addition, among those who experienced CR/CRh, seven patients (21%) had no residual detectable IDH1 mutations on polymerase chain reaction assay. Preliminary data also suggested that patients with relapsed or refractory AML with clearance of IDH1 mutations in bone-marrow mononuclear cells have longer durations of remission and longer overall survival than those without clearance of these mutations.

“In patients with complete remission and persistent detectable IDH1 mutations, the clinical significance and prognostic effect of ongoing molecular detection of IDH1 mutations remain unknown, but their presence suggests active and ongoing differentiation,” the authors noted. “Further evaluation of changes in the allelic burden of IDH1 mutations over time and evaluation of cooperating mutations at initiation and over time with ivosidenib therapy will be important avenues of future research.”

Limitations of the analysis include the lack of a comparator control group and the lack of evaluation of other ivosidenib treatment doses. Further research is required to determine single-agent ivosidenib’s effect in the broader AML population, Dr. DiNardo said. “I am excited to see the results of clinical trials investigating ivosidenib in combination with other effective antileukemia therapies, both in newly diagnosed patients with AML as well as in patients with relapsed/refractory AML,” she concluded.

The authors report financial relationships with Agios Pharmaceuticals, which also supported the study.


DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378:2386-98.