https://orcid.org/0000-0001-8506-0624
In this issue of Blood Advances, Cortes et al report encouraging outcomes in patients with isocitrate dehydrogenase 1 (IDH1)–mutated relapsed/refractory (R/R) or treatment-naïve high-risk myelodysplastic syndrome (MDS) treated with olutasidenib (OLUTA), a second-generation small molecule inhibitor targeting mutant isocitrate dehydrogenase 1.1 Given the limited availability of effective targeted agents for higher-risk MDS, particularly in the R/R setting after progression following hypomethylating agent (HMA) therapy, the emergence of an active and tolerable treatment such as OLUTA represents a significant advance for this molecularly-defined subgroup.
IDH mutations in myeloid malignancies have broad effects on epigenetics, differentiation, and metabolism; thus, they are attractive targets for therapeutic development.2 IDH1 inhibitors, including OLUTA, are highly active as monotherapy and in combination with HMAs in IDH1-mutated acute myeloid leukemia (AML), where IDH1 mutations are identified at a frequency of ∼7% to 8%.3-6 IDH1 mutations are less common in MDS, occurring in ∼3% to 4% of patients. The successful execution of this trial by Cortes et al, involving this rare molecular subgroup, is a testament to the shared strengths of international collaborations among investigators and study sites.
In the present analysis, OLUTA with or without azacitidine (AZA) yielded an overall response rate (ORR) of 59% (n = 13/22) and complete remission (CR) rate of 27% (n = 6/22). Among patients with a marrow CR (mCR) rate of 32% (n = 7/22), hematologic improvement was observed in 57%. An increased ORR was observed with OLUTA + AZA (n = 16) vs OLUTA monotherapy (n = 6) (69% vs 33%). Response rates were also higher among treatment-naïve patients (86%, n = 7) compared to those with R/R-MDS (47%, n = 15). The observed responses were durable, with a median duration of response of 14.6 months among those achieving CR or mCR and 20.5 months in patients attaining CR. Median overall survival (OS) was 27.2 months, including 27.5 months for OLUTA + AZA and 14 months for OLUTA monotherapy. In the 7 treatment-naïve patients, 24-month OS was 86%, whereas patients with R/R-MDS had a median OS of 16.3 months.
Considering R/R-MDS is associated with a median survival of <6 months, these data are highly encouraging.7 They mirror prior published outcomes observed with the IDH2 inhibitor enasidenib in R/R-MDS, supporting the broader concept of using these molecularly-targeted agents either alone or in combination in patients with MDS.8
Safety outcomes were generally favorable. Both OLUTA monotherapy and the OLUTA + AZA combination were tolerable, with low rates of nonhematologic adverse events and no treatment-related deaths. However, differentiation syndrome (DS), a known complication of differentiating agents including IDH1/2, FLT3, and menin inhibitors, occurred in ∼14% of patients.9 Although DS is more often recognized in AML, this finding underscores the importance of vigilance and early intervention in the MDS population.
With 2 active IDH1 inhibitors demonstrating efficacy in R/R-MDS populations, the landscape of IDH1 inhibition in myeloid malignancies is evolving rapidly, yet key questions remain.1,10 These questions include (1) selecting the optimal IDH1 inhibitor, (2) timing of inhibitor use (frontline vs at progression), and (3) whether monotherapy or combination therapy yields superior outcomes.
Cross-trial comparisons are inherently limited, but it is readily apparent that IDH1 inhibition is active in MDS. Ivosidenib (IVO), the first-in-class IDH1 inhibitor, demonstrated an ORR of 83.3% and CR rate of 38.9% in 18 evaluable patients. With long-term follow-up, the median duration of response in those achieving CR was not reached, and median OS was 35.7 months.10 OLUTA, with greater selectivity for mutant over wild-type IDH1 and activity against resistance-conferring second-site mutations, may offer advantages over IVO, although head-to-head comparisons are lacking.11
Similar to IVO, OLUTA showed activity following MDS progression on HMAs, suggesting utility in the second-line setting. Whether the upfront use of OLUTA (as monotherapy or in combination with AZA) could yield deeper or more durable responses remains unknown. Although the treatment-naïve cohort in the current analysis was small (n = 7), the ORR of 86%, CR rate of 71%, and median OS that has not been reached are compelling reasons for future study. Further evaluation of frontline OLUTA use in MDS is a question that is slated to be addressed in the upcoming IDH1-mutant MDS arm of the National Cancer Institute MyeloMATCH initiative.
The observed superiority of OLUTA + AZA over OLUTA alone (in terms of ORR [69% vs 33%], CR rate [31% vs 17%], and OS [27.5 vs 14 months]) suggests combination therapy is more effective than sequential use. Correlative studies will be imperative to understand if combination therapy overcomes resistance mechanisms to IDH1 inhibitor monotherapy. These results parallel findings in IDH1-mutant AML, where OLUTA + AZA has shown promising activity.4 Similarly, IVO + AZA led to a median OS of ∼29 months in an updated analysis of the phase 3 AGILE study in patients with newly diagnosed IDH1-mutated AML.5,6
Are IDH1 inhibitors such as OLUTA and IVO the Achilles’ heel of IDH1-mutant MDS? The data presented by Cortes et al make a strong case. In a disease with a checkered past of failed novel therapies, the activity of IDH1/2 targeted therapies provides a much-needed reason for optimism. Conducting large, randomized studies in this rare molecular subset of patients will be difficult. Nevertheless, the strength of these findings supports continued international collaboration and innovative trial design to further optimize the integration of these targeted therapies in IDH1-mutated myeloid neoplasms.
Conflict-of-interest disclosure: C.L. reports research funding from AbbVie and serves as a consultant or advisory board member for Bristol Myers Squibb, AbbVie, Rigel, Servier, Syndax, Astellas, Solu Therapeutics, and COTA Healthcare. L.W. declares no competing financial interests.
