A phase I study suggests that ivosidenib can induce remission in patients with relapsed or refractory acute myeloid leukemia characterized by IDH1 mutations. The drug spurred complete remission or complete remission with partial hematologic recovery in 30.4% of patients. The most common side effects of at least grade 3 were prolonged QT interval and IDH differentiation syndrome.

Enasidenib (Idhifa; Celgene) is approved for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with IDH2 alterations, but no targeted therapies are available for patients with IDH1-mutant disease. However, according to a recent study and presentation at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, IL, the investigational drug ivosidenib (Agios) may benefit these patients.

About 20% of patients with AML have IDH1 or IDH2 mutations. These alterations result in accumulation of R-2-hydroxyglutarate, which blocks reactions dependent on α-ketoglutarate and prevents differentiation of myeloid cells.

Because ivosidenib reduced R-2-hydroxyglutarate levels in animals, researchers enrolled 258 patients with AML, 179 of whom had refractory or relapsed disease, in a phase I/II trial. They assessed the effectiveness of ivosidenib in the first 125 patients with relapsed or refractory AML who received a daily dose of at least 500 mg. The overall response rate was 41.6%, and 30.4% of the patients had a complete remission or a complete remission with a partial hematologic recovery, meaning that the fraction of bone marrow cells that are blasts falls below 5%. “That's pretty good for a pill,” says co-author Richard Stone, MD, of Dana-Farber Cancer Institute in Boston, MA.

Overall survival after a median of 14.8 months of follow-up was 8.8 months. Among the patients who achieved a complete remission or complete remission with a partial hematologic recovery, 50.1% survived for 18 months.

The most common side effect of grade 3 or higher, affecting 7% of patients, was a prolonged QT interval, a disorder of the heart's electrical activity that can lead to arrhythmia in rare cases. This side effect was manageable, the researchers found.

IDH differentiation syndrome (IDH-DS), which occurs when malignant cells abruptly mature, affected 4.7% of the patients. IDH-DS also occurs in patients with AML after treatment with enasidenib and in other types of leukemia, notes Charles Schiffer, MD, of the Karmanos Cancer Institute in Detroit, MI, who wasn't connected to the study. “Leukemia doctors are now accustomed to recognizing it, and it's treatable with steroids, hydroxyurea, or both,” he says.

Co-author Courtney DiNardo, MD, of The University of Texas MD Anderson Cancer Center in Houston, notes that many patients were spared transfusions with the drug. Of the 84 patients who needed regular transfusions prior to the study's start, 29 went without them for at least 56 days, suggesting that the drug improves quality of life, she says.

“This is an exciting development and adds to the recent new therapies for AML, a disease whose standard therapy remained unchanged for 30 years,” says Aaron Schimmer, MD, PhD, of the University of Toronto in Canada.

Because of the strength of the findings, Mark Levis, MD, PhD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, MD, predicts that ivosidenib will be approved. “It will change how we manage these patients,” he says.

However, most patients who received the drug eventually relapsed, notes Alexander Perl, MD, of the University of Pennsylvania in Philadelphia. Thus, “it will need to be paired with other effective therapies and ideally moved earlier in treatment to optimize response duration and any impact on survival.” To that end, a phase III trial that combines the drug with azacitidine (Vidaza; Celgene) as a first-line therapy began last year. –Mitch Leslie