Background
Phase 1 single-arm substudy (AG120-C-001). 19 patients enrolled (18 efficacy-evaluable) with relapsed/refractory IDH1-mutated MDS after failure of standard-of-care therapies, including HMA failure. Ivosidenib (AG-120) is a first-in-class oral inhibitor of mutant IDH1, blocking production of the oncometabolite 2-hydroxyglutarate and restoring myeloid differentiation. IDH1 mutations occur in ~3.6% of MDS.
Interventions and follow up
Regimen: Ivosidenib 500 mg orally once daily continuously, 28-day cycles, until progression or intolerance (IDH1-mutated R/R MDS)
Primary endpoint: Safety; overall hematologic response rate and CR rate (IWG 2006)
Median follow up: NR (final phase 1 substudy report)
Primary endpoint: Safety; overall hematologic response rate and CR rate (IWG 2006)
Median follow up: NR (final phase 1 substudy report)
Results
CR + PR rate: 38.9% (7/18; 95% CI 17.3–64.3)
ORR (CR + PR + marrow CR): 83.3% (15/18; 95% CI 58.6–96.4)
Median OS: 35.7 months
Probability of CR duration ≥5 years (KM estimate): 68.6%
RBC transfusion independence (transfusion-dependent pts): 71.4%
Platelet transfusion independence: 75.0%
ORR (CR + PR + marrow CR): 83.3% (15/18; 95% CI 58.6–96.4)
Median OS: 35.7 months
Probability of CR duration ≥5 years (KM estimate): 68.6%
RBC transfusion independence (transfusion-dependent pts): 71.4%
Platelet transfusion independence: 75.0%
Adverse events
Overall: Treatment-related AEs in 42.1% (8/19); profile consistent with ivosidenib in AML.
Differentiation syndrome: Grade 2 in 2 patients (10.5%); no grade 3–4 reported.
Cardiac: Grade 1 QTc prolongation in 1 patient (5.3%).
Hematologic/Infections: No new safety signals; cytopenias and infectious complications consistent with the underlying R/R MDS population.
Differentiation syndrome: Grade 2 in 2 patients (10.5%); no grade 3–4 reported.
Cardiac: Grade 1 QTc prolongation in 1 patient (5.3%).
Hematologic/Infections: No new safety signals; cytopenias and infectious complications consistent with the underlying R/R MDS population.
Conclusions
Ivosidenib demonstrated clinically meaningful activity in R/R IDH1-mutated MDS, with an 83% overall response rate and durable complete remissions (68.6% probability of CR ≥5 years) at a median OS of nearly 3 years. Transfusion independence was achieved in the majority of transfusion-dependent patients, with a manageable safety profile.
Key Limitations
Very small single-arm phase 1 substudy (n=18–19) without a comparator, precluding formal efficacy conclusions or randomization-based inference. Highly molecularly selected R/R population (IDH1-mutated MDS is rare, ~3.6%), limiting generalizability. Median follow-up not reported and confidence intervals are wide. No prospective MRD endpoint. Survival benefit relative to standard salvage cannot be established from a single-arm dataset.
Clinical Context
Ivosidenib received FDA approval (Oct 2023) for relapsed/refractory IDH1-mutated MDS based on this substudy. It is approved in IDH1-mutated AML (newly diagnosed with azacitidine, and R/R). IDH1 mutation testing should be performed in MDS to identify candidates. ELN and emerging MDS recommendations support targeted IDH1 inhibition in this molecularly defined subset, particularly after HMA failure where outcomes are otherwise poor.