Rezlidhia (olutasidenib)

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

Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. NCT02719574.

The drug ibrutinib serves as a standard for comparison. The approach was shown accurate throughout a range of 3.0-60.0 ng ml-1 and correlation values of (r 2) ≥ 0.999.6 replicates including olutasidenib at 4 distinct QC levels were analyzed to determine intra-assay precision and accuracy; the Coefficient of variations (CV) were reported to be 3.41% to 0.58% to 0.31% to 0.36, and the accuracy ranged from 97.40, 99.69, 99.4, and 99.16%, respectively, for LOQQC, LQC, MQC, and HQC. In a pharmacokinetic investigation using rat plasma, this strategy has proven effective.

IDH1-inhibitors, such as ivosidenib and olutasidenib, block this aberrant metabolic pathway, allowing for differentiation and apoptosis of leukemia cells. Given the rarity of these mutations, comprehensive molecular testing remains essential to optimize therapeutic decision-making.

The results obtained from these clinical trials provide evidence that integrating oral targeted agents into the management of relapsed or refractory AML improves patient outcomes, especially for older or unfit patients who cannot undergo intensive chemotherapy. In conclusion, the episode demonstrates that the evolving use of IDH1 inhibitors, supported by rigorous clinical evidence, represents a promising advance in AML treatment by offering more precise, effective, and tolerable therapeutic options.

Furthermore, using a novel single cell measurable residual disease assay and digital PCR and qPCR for the detection of IDH1 and NPM1 mutations, we found no evidence of residual detectable leukemia. To our knowledge, this is the first report of an AML patient functionally cured by IDH1 inhibitor monotherapy.

P2, N=68, Not yet recruiting, M.D. Anderson Cancer Center

Following weighting, treatment with OLU versus IVO was associated with significantly higher rates of complete response (RD: 0.25; 95%CI: 0.01, 0.49), transfusion independence (RD: 0.27; 95%CI: 0.01, 0.53), and OS (HR: 0.33; 95%CI: 0.11, 0.94). Results suggest favorable effectiveness of OLU versus IVO in this population.

We discuss investigational therapies in the MDS pipeline, such as venetoclax, emavusertib, canakinumab and olutasidenib...We discuss how the identification of biomarkers of response to therapeutics may help guide clinical trial design for certain subsets of patients. Finally, we discuss how multicentre randomized trials can help facilitate the clinical rollout of emerging MDS therapeutics.