FDA Approves Ivosidenib for Relapsed or Refractory Myelodysplastic Syndromes with IDH1 Mutation

On October 24, 2023, the U.S. Food and Drug Administration (FDA) approved ivosidenib for adult patients with relapsed or refractory myelodysplastic syndromes (MDS) harboring isocitrate dehydrogenase-1 (IDH1) mutations (IDH1 mutations detected by an FDA-approved test).

The FDA also approved the Abbott RealTime IDH1 assay as a companion diagnostic device to identify patients eligible for treatment with ivosidenib.

The approval of this study was based on trial AG120-C-001 (NCT02074839), an open-label, single-arm, multi-center trial that enrolled 18 adult patients with relapsed or refractory MDS carrying IDH1 mutations. The IDH1 mutation was detected in peripheral blood or bone marrow through local or centralized diagnostic testing and retrospectively confirmed by the Abbott RealTime IDH1 assay.

The starting dose of ivosidenib is 500 mg once daily for 28 consecutive days, continued until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation. The median treatment duration was 9.3 months. One patient underwent stem cell transplantation following ivosidenib treatment.

Efficacy was determined based on the complete response (CR) or partial response (PR) rate, duration of CR+PR, and the conversion rate from transfusion dependence to independence. All observed responses were CRs. The CR rate was 38.9% (95% CI: 17.3, 64.3). The median time to CR was 1.9 months (range: 1.0-5.6 months), and the median duration of CR could not be estimated (range: 1.9-80.8+ months). Of the 9 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 6 (67%) became transfusion-independent for both RBC and platelets during the 56-day period post-baseline. Among the 9 patients who did not require RBC and platelet transfusions at baseline, 7 (78%) remained transfusion-free during the 56-day period post-baseline.

The most common adverse reactions are similar to those commonly observed with ivosidenib monotherapy in AML treatment. These include gastrointestinal toxicities (diarrhea, constipation, mucositis, and nausea), arthralgia, fatigue, cough, myalgia, and rash. Ivosidenib can also cause QTc prolongation. The prescribing information for ivosidenib contains a black box warning to alert healthcare professionals and patients about the risk of potentially life-threatening or fatal differentiation syndrome.