Olutasidenib Improves Survival in Myelodysplastic Syndrome
August 20, 2025
5 min read
Key takeaways:
Table of Contents
- Olutasidenib monotherapy or combination therapy may help certain patients with myelodysplastic syndrome achieve durable response.
- Many patients in the study achieved transfusion independence.
Olutasidenib could dramatically extend survival and reduce dependence on transfusions for certain patients with myelodysplastic syndrome, according to results of a phase 1/2 investigation.
Individuals with higher-risk disease and an IF1 mutation who received olutasidenib (Rezlidhia, Rigel Pharmaceuticals) as monotherapy or as part of combination therapy had a median OS of more than 2 years.
Data derived from Cortes JE, et al. Blood Adv. 2025;doi:10.1182/bloodadvances.2025016718.
Additionally, median duration of remission lasted more than 20 months and more than 60% of patients achieved transfusion independence.
Justin M. Watts
“When you see a patient with myelodysplastic syndrome with an IF1 mutation, you should immediately think about an IDH1 inhibitor,” Justin M. Watts, MD, associate professor of medicine in the division of hematology and chief of the leukemia section at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, told Healio.
Standard ‘has not changed’
In the U.S., 4.5 per 100,000 individuals are diagnosed with myelodysplastic syndrome (MDS) annually, according to study background.
Risk rises substantially as people get older (ages 70-79 years, 26.9 per 100,000).
Patients with low-risk disease are predominantly treated to improve cytopenia. Those with higher-risk MDS typically receive treatment with a hypomethylating agent such as azacitidine or decitabine.
Individuals with relapsed/refractory disease have a median OS around 6 months, according to Watts.
“The standard of care has not changed in 30 years,” Watts said of treatment with azacitidine. “It’s not a bad drug, that’s why it’s approved. It works in some patients, but only about 20% of patients in the front line have a real good response and another handful have some response, and the durability is suspect.
“The issue with MDS is it doesn’t have as many targetable mutations as acute myeloid leukemia or some other cancers, but IF1 or IDH2 are notable exceptions,” he added. “When the patient has that mutation, they tend to be very dependent on it.”
Approximately 3% to 4% of patients with MDS have an IF1 mutation.
In 2022, the FDA approved olutasidenib, an IF1 inhibitor, for certain patients with AML based on research in which Watts and colleagues participated.
That study also enrolled individuals with MDS.
“One thing we noticed about the patients with AML who have very long durability of response and survival with olutasidenib is that they resemble more of an MDS-like mutational pattern,” he said.
The investigation included 22 adults (median age, 74 years; range, 59-87; 59% men) with intermediate- to very high-risk MDS and an IF1 mutation, but no prior treatment with an IF1 inhibitor.
Participants could have newly diagnosed (n = 7) or relapsed/refractory disease (n = 15).
They received either olutasse monotherapy (n = 6) or in combination with azacitidine (n = 16) based on physician recommendation.
After a phase 1 dose-escalation stage, researchers recommended a phase 2 dose of 150 mg olutasidenib twice daily for continuous 28-day cycles regardless of arm. Adults in the combination cohort also received 75 mg/m² azacitidine daily for 7 days.
Safety and complete remission served as primary endpoints. Overall response rate, time to response, duration of response, EFS, OS and transfusion independence (56 days after baseline without transfusion) served as secondary endpoints.
‘Very strong survival numbers’
After a median follow-up of 53.8 months, the overall cohort had an OS of 27.2 months (95% CI, 6-37) and a 1-year survival probability of 68% (95% CI, 45%-83%).
Patients in the combination arm had a higher median OS than those who got monotherapy (27.5 months vs. 14 months).
Newly-diagnosed participants did not reach median OS and had 86% survival at 1 and 2 years.
“Frontline patients did remarkably well,” Watts said.
Patients with relapsed/refractory disease had a median OS of 16.3 months (95% CI, 3.1-36.6), 60% survival at 1 year and 43% at 2 years.
“Those are very strong survival numbers,” Watts said.
The overall cohort had an ORR of 59%, complete remission occurred in 27% of participants and 32% achieved marrow complete remission.
The overall cohort had a median duration of response of 20.5 months (95% CI, 4.9-not reached).
Among patients that had marrow complete remission, 57% had hematologic improvement in at least one lineage.
In the monotherapy arm, only three patients received the recommended dose. Each of them achieved a complete remission, marrow complete remission and hematologic improvement.
In the combination group, participants who had treatment-naïve disease had an ORR of 100% compared with 54.6% for those who had relapsed/refractory MDS. Additionally, 80% of complete remissions in the arm had been newly diagnosed patients.
Among participants dependent on red blood cell transfusions, 62% had 56-day transfusion independence and 23% remained dependent.
“That is another strong sign of true biological activity in MDS,” Watts said. “When you see real, sustained blood count improvement and transfusion independence, you know your drug’s working.”
All participants experienced at least one treatment-emergent adverse event and 95% had a grade 3 or worse event.
The most common any-grade treatment-emergent adverse events included fatigue (67% in monotherapy; 63% in combination), nausea (67%; 56%) and arthralgia (67%; 31%). Several patients (56%) in the combination group also experienced constipation.
Common grade 3 or worse treatment-emergent adverse events in the monotherapy arm included thrombocytopenia (33%) and neutropenia (33%). The most frequent in the combination group included neutropenia (38%), febrile neutropenia (31%) and thrombocytopenia (25%).
“IDH inhibitors are one of the best tolerated drugs ever used in leukemia of any class,” Watts said. “They are very well tolerated, even compared to other kinase inhibitors. You don’t see a lot of skin or GI toxicity or myelosuppression. They each have some idiosyncratic side effects that are manageable. For olutasidenib, one thing that we did see in about 10% of patients was [elevated liver enzymes] of significance, and if that happened, we had to hold and then resume the drug, sometimes at a lower dose. It usually got better, and patients were able to continue the study.”
“Lastly, the class effect of differentiation syndrome occurs in about 10% to 15% of patients with MDS or AML and requires close monitoring but is manageable with standard supportive care,” he added.
At the end of the study, 13.6% of patients stayed on treatment.
Researchers acknowledged study limitations, including the small sample size.
‘Common-sense standard of care’
Watts does not expect a randomized phase 3 trial for olutasidenib due to the limited patient population.
However, the collective data suggest olutasidenib or other IF1 inhibitors should be part of treatment for individuals with higher-risk disease and an IDH1 mutation.
It should be “common-sense standard of care,” Watts said.
“The next steps are not confirming anything else in MDS or AML with single agent or with azacitidine,” he added. “It’s how do we cure patients?”
Watts and colleagues have reported on one patient who has been on olutasidenib for nearly a decade and remains in remission, and she is not alone.
“It’s a significant minority,” he said.
Combining IDH inhibitors with azacitidine and other agents, such as venetoclax (Venclexta; AbbVie, Genentech), particularly in the first-line setting, could benefit more patients.
Other mutations could be targeted, too.
“We’re blessed to have all these new agents in AML to combine, sequence and to play with to improve outcomes in patients, all that have their own individual activity,” Watts said. “How to best combine all that to maximize cure rate is what we’re trying to do.”
References:
For more information:
Justin M. Watts, MD, can be reached at jxw401@miami.edu.
Sources/Disclosures
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Disclosures:
Watts reports receiving research funding from Immune System Key Ltd, Rigel and Takeda, and consulting for or serving on an advisory board for Aptose, Astellas, Celgene/Bristol Myers Squibb, Daiichi-Sankyo, Genentech, Rafael Pharma, Reven Pharma, Rigel, Servier and Takeda. Please see the study for all other authors’ relevant financial disclosures.