Rezlidhia (olutasidenib)

Inhibitors of mutated IDH1 and IDH2, vorasidenib, ivosidenib, olutasidenib, and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML. In this review, we mainly focus on IDH inhibitors in leukemia therapy, including the discovery, structure optimization, activity of IDH inhibitors, and applications, which provided the reference for the discovery of new anticancer agents.

P1, N=15, Recruiting, Virginia Commonwealth University | Not yet recruiting --> Recruiting | Trial completion date: Oct 2029 --> Oct 2030 | Trial primary completion date: Oct 2027 --> Oct 2028

Olutasidenib was well tolerated and conferred disease control in cCS. Study limitations include open-label design and low patient sample due to rarity of cCS.

P2, N=28, Recruiting, University of California, Davis | Not yet recruiting --> Recruiting

Olutasidenib-based therapy demonstrated 100% response rates in previously untreated IDH1-mutated AML and MDS and modest efficacy in heavily pretreated R/R AML and MDS. Durable remissions occurred in select responders and with stem cell transplant. Further evaluation of olutasidenib as frontline therapy in IDH1-mutated AML or MDS and as a bridge to transplant is warranted.

P2, N=28, Not yet recruiting, University of California, Davis

P1, N=15, Not yet recruiting, Virginia Commonwealth University | Initiation date: Oct 2025 --> Feb 2026

P2, N=132, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Feb 2026 --> May 2026

These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R mIDH1 AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.

P2, N=68, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Venetoclax, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has shown promise in clinical trials but requires further validation. Isocitrate dehydrogenase 1 (IDH1) inhibitors, including ivosidenib and olutasidenib, have demonstrated efficacy and tolerability, while ongoing investigations explore other novel agents like IDH2 inhibitors and FMS-like tyrosine kinase 3 (FLT3) inhibitors. By summarizing the latest advancements, this review emphasizes the importance of developing safe, effective, and personalized therapies to improve outcomes and quality of life for older patients with HR-MDS, with a focus on age-specific clinical trials.

P1, N=15, Not yet recruiting, Virginia Commonwealth University