Olutasidenib and Azacitidine for Myelodysplastic Syndromes with IDH1 Mutations

Understanding the role of IDH1 mutations

Isocitrate dehydrogenase 1 (IDH1) mutations are found in a small but important subset of blood cancers. They occur in about 3% to 4% of people with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) and in around 9% of people with myeloproliferative neoplasms (MPN). 

Research has shown that these mutations are linked with shorter survival and a higher risk of transformation into acute myeloid leukemia (AML). While IDH1 inhibitors are already part of AML treatment, there are currently no approved IDH1-targeted options for MDS, CMML, or MPN outside of clinical trials.

During the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, researchers presented the results of a phase II clinical trial that tested a combination of olutasidenib (Rezlidhia, Rigel Pharmaceuticals) and the chemotherapy azacitidine for these patients.  

Introducing olutasidenib in combination therapy

Olutasidenib is already approved to treat relapsed or refractory AML that has an IDH1 mutation.. In prior studies, olutasidenib combined with azacitidine showed an overall response rate of 51% in relapsed or refractory AML. In MDS, results have been encouraging, with response rates of 86% in patients who have not received previous treatment and 47% in those previously treated.

Because of these results and because olutasidenib is generally well-tolerated and does not damage healthy dividing cells the way traditional chemotherapy does, researchers are continuing to investigate this drug for people with other cancers. At the 2025 American Society of Clinical Oncology (ASCO) Annual meeting  researchers shared a new phase II study that will measure the effectiveness of olutasidenib for patients with higher-risk MDS, CMML, or advanced MPN who have an IDH1 mutation.

About the new phase II study

The new multicenter study led under the MD Anderson Cancer Center–Rigel Research Alliance is evaluating the combination of olutasidenib and azacitidine in this patient population. The trial (ClinicalTrials.gov ID: NCT06597734) opened in January 2025 and plans to enroll 45 patients across 5 to 6 centers in the United States.

Patients will be divided into two groups:

• Treatment-naïve group: Patients who have not previously received therapy.
• Previously treated group: Patients who have already undergone treatment, including up to 5 patients with MPN in each group.
  
  

To be eligible, participants must have confirmed IDH1 mutations, acceptable organ function, and either higher-risk MDS or CMML (based on International Prognostic Scoring Systems) or an advanced MPN with at least 10% bone marrow blasts.

Treatment plan and assessments

Patients will receive:

• Azacitidine 75 mg/m² intravenously or subcutaneously on days 1 through 7 of each treatment cycle.
• Olutasidenib 150 mg orally twice daily continuously.
  
  

Responses will be evaluated after the first cycle, then every three cycles through cycle 12, and every 12 cycles thereafter. Once treatment ends, patients will continue in follow-up every three months for three years to assess survival outcomes.

Study objectives

The primary objective is to measure overall response rates using recognized international criteria for MDS, MDS/MPN, and AML depending on the diagnosis.

The secondary objectives include:

• Rates of complete remission
• Safety and tolerability of the combination
• Overall survival and progression-free survival
• Duration of response
• Changes in the size of the IDH1-mutated cell population over time

Why studying an IDH1 inhibitor for MDS, CMML, and advanced MPNs matters 

This is the first formal trial exploring an IDH1 inhibitor in combination with azacitidine for higher-risk MDS, CMML, and advanced MPN. Since no IDH1-targeted regimens are currently approved for these diseases, results from this study could provide important evidence to expand treatment options.

For patients with IDH1-mutated MDS, CMML, or advanced MPN, the combination of olutasidenib and azacitidine is being carefully studied as a potential therapy. The results may clarify whether IDH1 inhibition can improve response rates and extend survival beyond what is currently possible.

If you or a loved one has one of these conditions, consider discussing this clinical trial with your care team. You can find additional details here: NCT06597734. Staying informed about new therapies and trial opportunities can help guide treatment planning. Keep browsing for personalized clinical trial options, create a free account and set your clinical trial preferences in our Clinical Trial Finder. 

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