Results from a phase Ib/II study presented at the 23rd Congress of the European Hematology Association suggest that combining an IDH inhibitor (ivosidenib or enasidenib) with the hypomethylating agent azacitidine leads to high response rates in older patients with previously untreated acute myeloid leukemia (AML).
According to lead author and presenter Courtney D. DiNardo, MD, from the University of Texas MD Anderson Cancer Center in Houston, “the combination of azacitidine with an oral IDH inhibitor was well tolerated, and randomized studies are ongoing,” she told ASH Clinical News.
The early-phase trial enrolled adults with mutant IDH-positive, newly diagnosed AML who had an Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤2 and were considered ineligible for intensive chemotherapy.
Dr. DiNardo presented data from the dose-finding and dose-expansion phases of the trial, during which 29 participants received treatment in continuous 28-day cycles. All patients received azacitidine 75 mg/m2 for a total of seven days plus an IDH inhibitor at one of the following dose levels:
- once-daily ivosidenib 500 mg (n=23)
- once-daily enasidenib 100 mg (n=3)
- once-daily enasidenib 200 mg (n=3)
Among the patients receiving ivosidenib (median age = 76 years; range = 74-82 years) and enasidenib (median age = 68 years; range = 65-76 years), 82 percent and 83 percent, respectively, presented with an ECOG score of 1.
As of March 15, 2018 (data cutoff), 19 patients (17 in the ivosidenib arm and 2 in the enasidenib arm) remained on the trial.
“Treatment-emergent AEs were generally consistent with what has been shown for IDH inhibitors and azacitidine alone,” Dr. DiNardo reported.
In the ivosidenib arm, the most common AEs were nausea (n=14), anemia (n=12), and thrombocytopenia (n=11), while the most common grade 3-4 AEs were anemia and thrombocytopenia (n=10 each) and febrile neutropenia (n=9). In the enasidenib arm, the most common AEs were hyperbilirubinemia (n=5) and abdominal pain, nausea, vomiting, and pyrexia (n=4 each). The most common grade 3-4 AEs in this arm were anemia and thrombocytopenia (n=3 each), followed by hyperbilirubinemia, neutropenia, lung infection, and pneumonia (n=2 each).
According to the investigators, the incidence of enasidenib-related indirect bilirubin elevations and grade 1 to 2 gastrointestinal AEs in this study were most likely a result of “off-target inhibition of the UGT1A1 enzyme.”
At data cutoff, 15 of the ivosidenib-treated patients (65%) and three of the enasidenib-treated patients (50%) responded to treatment. Responses included:
- complete remission (CR): 10 patients (44%) in the ivosidenib arm and 3 patients (50%) in the enasidenib arm
- CR with incomplete count recovery: 5 (22%) and 0
In addition, three participants in the ivosidenib group and one in the enasidenib group had morphologic leukemia-free state.
To measure depth of response, the researchers also evaluated IDH clearance in 27 patients with sequencing data available. IDH1 mutation clearance was observed in seven of 21 ivosidenib-treated patients and three of the six enasidenib-treated patients – all of whom had responded to treatment.
A limitation of this early-phase study includes its relatively small sample size, which may reduce generalizability of the findings to the larger population of patients with newly diagnosed AML. There also was no comparison arm.
Based on these initial findings, the researchers are now enrolling patients in the phase II and III AGILE study portions, which are evaluating outcomes associated with enasidenib plus azacitidine and ivosidenib plus azacitidine, respectively.
Dr. DiNardo added that she would like to see further research to answer the questions of “whether development of IDH minimal residual disease–negative status can be used to predict durable responses, and whether certain computations are predictive of response or resistance to this combination.”
Dr. DiNardo reports financial relationships with Celgene and Agios, the manufacturer of ivosidenib and enasidenib.
DiNardo CD, Stein AS, Stein EM, et al. Mutant IDH (MIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML). Abstract #S1562. Presented at the EHA 23rd Congress, June 17, 2018; Stockholm, Sweden.