Ivosidenib Plus Venetoclax With or Without Azacitidine for IDH1-Mutated AML

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Combination therapy with the isocitrate dehydrogenase 1 (IDH1) inhibitor ivosenidib plus the BCL2 inhibitor venetoclax with or without the chemotherapeutic agent azacitidine showed activity in patients with IDH1-mutated acute myeloid leukemia (AML) in a phase Ib/II trial. The results of the study—presented by Lachowiez et al during the Hematologic Malignancies Oral Abstract Session of the ASCO20 Virtual Scientific Program (Abstract 7500)—may support a novel course of action for patients with AML harboring an IDH1 mutation—a group who have historically had few treatment options.

Mutations in the IDH1 gene lead to myeloid differentiation arrest and subsequent induction of leukemia. Ivosidenib, as an IDH1 inhibitor, is a well-tolerated oral therapy that aims to interrupt this leukemogenic process.    

The combination of venetoclax and azacitidine was previously established to be well tolerated and effective against newly diagnosed AML, and ivosidenib is approved as a single agent for relapsed IDH1-mutated AML. This trial sought to evaluate the safety, tolerability, and response rate of adding ivosidenib to either venetoclax alone as an oral doublet, or to the combination of azacitidine/venetoclax to treat this subset of patients with AML and a specific genetic mutation.


  • Across all treatment groups, the composite complete remission rate was 78% overall and 100% for treatment-naive patients.
  • Half of the patients who achieved complete remission also were negative for minimal residual disease.

“This trial is the manifestation of remarkable basic and translational work that is resulting in improved clinical outcomes for patients,” said lead author Curtis Lachowiez, MD, hematology fellow at The University of Texas MD Anderson Cancer Center, in an institutional statement. “The triplet combination may ultimately result in a new, effective therapeutic regimen. As the median age at AML diagnosis is 68, these findings are particularly important for older [patients with] AML who may not be fit enough to receive the aggressive cytotoxic chemotherapy regimens historically used to treat AML.”

Study Methods and Findings

Patients with AML or high-risk myelodysplastic syndrome were assigned one of three treatment cohorts: ivosidenib plus venetoclax at 400 mg, ivosidenib plus venetoclax at 800 mg, or ivosidenib plus venetoclax at 400 mg plus azacitidine.

Across all treatment groups, the composite complete remission rate was 78% overall and 100% for treatment-naive patients. Half of the patients who achieved complete remission also were negative for minimal residual disease.

The median time to best response was 2 months. Of the 18 evaluable patients, 9 remain enrolled in the study, and 3 proceeded to receive a stem cell transplant following complete remission.

Courtney DiNardo, MD

Courtney DiNardo, MD

“To our knowledge, azacitidine plus venetoclax and azacitidine plus ivosidenib ‘doublets’ are effective but not curative for newly diagnosed [patients with] IDH1-mutated AML, and patients still ultimately relapse. This triplet combination trial aims to determine whether this regimen leads to deeper responses and even curative therapy in some patients,” said Courtney DiNardo, MD, Associate Professor of Leukemia at MD Anderson and the study’s senior author. “Additionally, this trial evaluates the oral ivosidenib plus venetoclax doublet for the first time, and we hope patients will benefit from this outpatient regimen.”

Based on a patient’s molecular profile, their care team may be able to decide on options like closer monitoring or earlier transition to transplant for high-risk patients. Further, as in the case of patients with molecular mutations associated with favorable responses, the care team may be able to prescribe tailored therapeutic combinations, leading to durable remissions and potential cures.

“This study is exciting because it displays that we are able to tailor therapy for…patients based on their molecular profile,” said Dr. Lachowiez. “While some mutations have traditionally been associated with poor outcomes, we can now identify certain subgroups of patients with genetic mutations who are more likely to respond to a specific therapy, and then we can design a treatment and follow-up plan to best suit them.”

Study accrual is continuing, and the research team is conducting additional follow-up to elucidate the biomarkers and potential duration of response.

Disclosure: This study was funded via The Lloyd Family Clinical Scholar V Foundation grant. For full disclosures of the study authors, visit

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