The Argument for Targeted Therapy in IDH1 Mutated Myelodysplastic Syndromes (MDS): Poor Outcomes Post-Hypomethylating Agent Failure in Higher Risk MDS and Reduced Leukemia Free Survival in Lower Risk MDS
Authors: Abuhelwa Ziad , Al Ali Najla H. , Xie Zhuoer , Chan Onyee , Yun Seongseok , Kuykendall Andrew T. , Walker Alison R. , Lancet Jeffrey E , Padron Eric , Sallman David , Komrokji Rami S. 
Published: December 2024

Background
IDH1 mutation is described in 3-5% of MDS patients (pts) and is enriched among those with neutropenia. Pts with higher risk MDS (HR-MDS) typically have poor outcomes post hypomethylating agent (HMA) failure, with a median overall survival (OS) of 4-6 months. Ivosidenib was approved for relapsed and refractory IDH1-mutant (MT) MDS, demonstrating a median OS of 3 years in a small cohort of pts, highlighting its potential efficacy. The historical outcome of IDH1-MT HR-MDS post-HMA failure is not well known. Similarly, in lower risk MDS (LR-MDS), we previously reported that IDH1 mutation is enriched among 9% of pts who progressed directly to acute myeloid leukemia (AML). The impact of IDH1 mutation among LR-MDS is not well characterized.
Methods
We retrospectively analyzed the outcomes of a large cohort of MDS pts. Our study aimed to compare outcomes between IDH1-MT and wild-type (WT). We examined 2 separate cohorts comparing IDH1-MT vs. WT. Cohort (A): HR-MDS (intermediate, high, and very high risk by IPSS-R) to assess response of IDH1-MT MDS to HMA, provide historical data on outcomes post-HMA failure and to assess the impact of IDH1 inhibitor use in real-world settings post-HMA failure. Cohort (B): LR-MDS (very low and low by IPSS-R) to assess impact of IDH1 mutation on OS and leukemia transformation.
Results
Cohort (A): A total of 1,057 HR-MDS pts who received frontline HMA therapy were included. IDH1 mutations were detected in 32 pts (3%), with the R132C mutation being the most common (50%). Age, white blood cell count, absolute neutrophil count, hemoglobin, platelets count, and bone marrow blast percentages were comparable between IDH1-MT and IDH1-WT groups. Mutations of EZH2 (12.5% vs. 4.6%), DNMT3A (37.5% vs. 0.1%), and CBL (6.3% vs. 2%) were more frequent in IDH1-MT cases (p&lt;0.05), whereas ASXL1 mutations (22.7% vs. 6.3%) were more common in IDH1-WT (p&lt;0.05). The upfront HMA regimens included azacitidine (61.5%), decitabine (14.4%), oral decitabine (1.5%), HMA with venetoclax (11.1%), and other HMA combinations (11.5%). Complete response rates to HMA therapy were similar between IDH1-MT and WT pts (16% vs 14%, p=0.78). Following HMA therapy failure, the median OS was 10 months: 9.6 months for IDH1-MT and 10.3 months for IDH1-WT pts. Four IDH1-MT pts received IDH1 inhibitors post-HMA failure (ivosidenib, n=3; olutasidenib, n=1), showing a significantly improved median OS of 28.6 months compared to 5.1 months for those who did not receive IDH1 inhibitors (n=28) (p&lt;0.05).
Cohort (B): Among 1,321 LR-MDS pts, we identified 37 (2.8%) with IDH1 mutation. Baseline characteristics were similar between IDH1-MT and WT groups except for younger age and leukopenia in the IDH-1 MT pts. More pts were upstaged to higher risk by IPSS-M among IDH1-MT (35% vs. 16% WT, p=0.008). SRSF2 and RUNX-1 were more observed among IDH1-MT pts. No difference in median OS between IDH1-MT and WT (92 vs. 75 months, p=0.25). Leukemia free survival (LFS) was not reached in IDH1-WT compared to 92 months in IDH1-MT pts (p = 0.006). The rate of AML transformation was higher in IDH1-MT (27% vs 11%, p=0.003). No difference in response to LR-MDS therapies was observed and many pts were in observation until disease progression.
Conclusion
For HR-MDS, response to HMA therapy is similar between IDH1-MT and WT pts. Historically, the median OS for IDH1-MT MDS post-HMA failure without IDH1 inhibitor is poor (5.1 months). However, IDH1 inhibitors significantly improve survival in IDH1-MT pts in real world data (OS 28.6 months). In IDH1-MT LR-MDS, a higher rate of AML transformation and worse LFS are observed. Our data provide the historical outcomes for IDH1-MT HR-MDS post-HMA and provide rational to target IDH1 mutation among LR-MDS given high rate of leukemia transformation.