Positive Results With Ivosidenib in Patients With High-Risk, Previously Treated AML

Treatment with ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, led to durable remissions among people with relapsed or refractory, IDH1-mutated acute myeloid leukemia (AML), according to results from a phase I, dose-escalation and -expansion study presented at the 2018 ASCO Annual Meeting.

Daniel A. Pollyea, MD, MS, from the University of Colorado School of Medicine, reported the results, which were published simultaneously in The New England Journal of Medicine.

In February 2018, the U.S. Food and Drug Administration (FDA) granted priority review to ivosidenib for the treatment of relapsed or refractory disease with an IDH1 mutation, based on earlier results from this ongoing phase I trial that were presented at the 2017 ASH Annual Meeting.

A total of 258 patients had received ivosidenib, at doses ranging from 100 mg twice-daily to 1,200 mg once-daily; 179 (median age = 67 years; range = 18-87 years) had received 500 mg once daily in continuous 28-day cycles.

The median number of prior therapies was two (range = 1-6), and most participants had relapsed/ refractory AML that was in second or later relapse, had relapsed following hematopoietic cell transplantation (HCT), or was refractory to induction or reinduction (n=126).

As of November 10, 2017 (data cutoff), 17 patients (9.5%) who received ivosidenib 500 mg remained on treatment, for a median treatment duration of 3.9 months (range = 0.1-39.5 months). The most common causes for treatment discontinuation were:

  • progressive disease (n=92; 51.4%)
  • adverse event (AE; n=27; 15.1%)
  • HCT (n=17; 9.5%)
  • death (n=10; 5.6%)

The authors reported that the most common adverse events (AEs) of any grade (occurring in ≥25% of patients) were: diarrhea (33.5%), leukocytosis (31.3%), nausea (31.3%), febrile neutropenia (29.1%), fatigue (28.5%), and prolonged QT (25.7%).

Most of these AEs were grades 1 or 2 and were considered unrelated to ivosidenib treatment. The most common grade ≥3 AEs included febrile neutropenia (29.1%), anemia (20.1%), and prolonged QT (10.1%).

Nineteen patients (10.6%) experienced IDH differentiation syndrome (IDH-DS), an AE that also was reported in clinical trials of the IDH2 inhibitor enasidenib. IDH-DS was grade ≥3 in nine of these patients (5.0%), and six patients (3.4%) discontinued ivosidenib because of IDH-DS.

“This is what we would expect the adverse event profile to be in a cohort of patients with relapsed/refractory AML,” Dr. Pollyea said. “A few patients had to have study drug held, but there were no cases of dose reduction or permanent discontinuation and no deaths from IDH-DS.”

He added that, even among people who developed IDH-DS, most responded to ivosidenib, “so the message is that supportive care and continued treatment can allow for patients to ultimately respond.”

The primary efficacy endpoint was complete remission rate (CR; defined as absolute neutrophil count >0.5×109/L and platelet count >50×109/L) and CR with partial hematologic recovery (CRh).

Efficacy Outcomes With Ivosidenib 500 mg/Day

The combined CR/CRh rate was 31.8 percent, which included CR in 43 patients (24%). The median duration of CR/CRh was 8.2 months (range = 5.6- 12.0 months), and patients achieved CR/CRh within a median of 2.0 months (range = 0.9-5.6 months). Additional response data, including overall response (secondary endpoint) are presented in the TABLE.

After a median follow-up of 15.3 months (range = 0.2-39.5 months), median overall survival was nine months (range = 7.1-10 months), and 18.8 months (range = 14.2 months to not estimable) in patients who achieved CR/CRh.

Among the 91 patients who were platelet transfusion–dependent and 97 who were red blood cell transfusion-dependent, the overall rate of transfusion independence (defined as no transfusion for at least one 56-day period) was 38.5 percent and 42.3 percent, respectively. Transfusion independence was observed across all response categories, the investigators noted. Among those who achieved a lower-degree response or no response at all, 17.5 percent became platelet transfusion independent and 23.7 percent red blood cell transfusion independent, “which is obviously a big achievement with regard to quality of life.”

In a preliminary analysis of minimal residual disease in this cohort, single-agent ivosidenib 500 mg was “able to completely eradicate evidence of the IDH1 clone in 23 percent (n=11/47) of patients who had achieved a complete remission.” Depth of response also was associated with clinical outcomes, durability, and survival, which were improved for all patients who responded and were able to clear the IDH1 mutations, Dr. Pollyea added.

The study’s findings are limited by its single-arm and unblended design. Dr. Pollyea noted that, based on results of ivosidenib in this patient population, the drug is being evaluated in patients with previously untreated AML.

The authors report financial relationships with Agios, the manufacturers of ivosidenib.


Pollyea DA, Dinardo CD, de Botton S, et al. Ivosidenib (IVO; AG-120) in mutant IDH1 relapsed/ refractory acute myeloid leukemia (R/R AML): results of a phase 1 study. Abstract #7000. Presented at the 2018 ASCO Annual Meeting, June 2, 2018; Chicago, IL.