Ivosidenib Plus Azacitidine in Newly Diagnosed IDH1-Mutant Acute Myeloid Leukemia

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In a phase Ib study reported in the Journal of Clinical Oncology, Courtney D. DiNardo, MD, and colleagues found that the combination of ivosidenib and azacitidine produced a high response rate in patients with newly diagnosed isocitrate dehydrogenase 1 (IDH1)-mutant acute myeloid leukemia ineligible for intensive induction therapy.

Ivosidenib is currently approved for treatment of IDH1-mutant AML. As noted by the investigators, preclinical evidence has suggested that the addition of azacitidine to ivosidenib may augment IDH1-mutant inhibition-related differentiation and apoptosis.

Courtney D. DiNardo, MD

Courtney D. DiNardo, MD

Study Details

In the international multicenter study, 23 patients were enrolled between June 2016 and November 2017 and received ivosidenib plus azacitidine, including 7 in a dose-finding phase and 16 in an expansion phase. Standard doses of ivosidenib and azacitidine were selected as starting doses, with patients receiving oral ivosidenib at 500 mg once daily in continuous 28-day cycles and subcutaneous azacitidine at 75 mg/m2 on days 1 to 7 of each cycle. The median age of the patients enrolled was 76 years (range = 61–88 years).


No dose-limiting toxicities were observed during the dose-finding phase, with ivosidenib at 500 mg once daily being selected as the recommended dose in combination with azacitidine.

Grade ≥ 3 adverse events occurred in 23 (100%) of 23 patients, with the most common being thrombocytopenia in 61% (treatment-related in 13%), anemia in 43% (treatment-related in 13%), febrile neutropenia in 43%, neutropenia in 30% (treatment-related in 22%), and sepsis in 22%. Treatment-related grade ≥ 3 QT prolongation occurred in 13%.

Serious adverse events occurring in two or more patients were febrile neutropenia in nine, IDH differentiation syndrome in three, sepsis in three, pyrexia in three, lung infection in two, pneumonia in two, and syncope in two.  Adverse events led to hospitalization in 65% of patients. Adverse events of special interest included any-grade IDH differentiation syndrome (17%), any-grade QT prolongation (26%), and grade ≥ 3 leukocytosis (9%).


Median treatment duration was 15.1 months (range = 0.3–32.2 months), with 10 patients remaining on treatment as of February 2019. Response was observed in 18 (78.3%) of the 23 patients, with complete remission observed in 14 (60.9%) and complete remission with incomplete hematologic or platelet recovery in 2 (8.7%). At median follow-up of 16 months, median duration of response had not been reached (lower bound of 95% confidence interval = 10.3 months).


  • Response was achieved in 78.3% of patients, with complete remission in 60.9%.
  • IDH1 mutation clearance in bone marrow mononuclear cells was observed in 71% of patients with complete remission.

At a median follow-up of 16.1 months, median overall survival was not reached. Estimated overall survival at 12 months was 82.0%.

IDH1-mutant clearance in bone marrow mononuclear cells was observed in 11 (69%) of 16 patients with complete remission (clearance in 71%)/complete remission with incomplete hematologic or platelet recovery, with an additional patient having clearance in peripheral blood mononuclear cells only. Of the four without clearance, three exhibited a reduction in IDH1-mutant variant allele frequency levels to < 1%. IDH1-mutant clearance was not observed in any patient without clinical response.

The investigators concluded: “Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving IDH1 mutation clearance.”

Dr. DiNardo, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Agios Pharmaceuticals and Bristol Myers Squibb. For full disclosures of the study authors, visit

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