Background and Significance: Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal myeloid disorders that primarily affect older adults. They are characterized by ineffective hematopoiesis and varying degrees of cytopenias, with variable risk of transformation to acute myeloid leukemia (AML). According to the International Prognostic Scoring System (IPSS), patients with MDS can be stratified into lower-risk (LR) and higher-risk (HR) disease categories. Treatment options for patients with LR-MDS and cytopenias include a range of drugs, such as hypomethylating agents (HMAs). In contrast, for patients with HR-MDS, HMAs remain the only standard-of-care treatment option. In treatment-naive MDS, the combined complete remission (CR) and partial remission (PR) rates with azacitidine (AZA) range from 16%–22%. These modest remission rates, along with the limited duration of remission (DOR), underscore an unmet clinical need in this patient population.

Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is approved by the FDA for treatment of adult patients with relapsed/refractory MDS. In the pivotal AG120-C-001 MDS substudy (NCT02074839), IVO treatment showed an acceptable safety profile and led to durable remissions, with a CR+PR rate of 38.9% (95% CI 17.3%, 64.3%); all responses were CR (DiNardo, Blood Adv 2024;8:4209). In the phase 2 IDIOME study, IVO monotherapy resulted in a CR+PR rate of 72% for patients with previously untreated mIDH1 HR-MDS; after a median follow-up of 25.2 months, the median overall survival (OS) and median DOR were not reached (Sebert, HemaSphere 2024;8[S1]:S182). The objective of the PyramIDH study (NCT06465953) is to confirm the safety and efficacy of IVO monotherapy in a larger cohort of patients with HMA-naive mIDH1 MDS.

Study Design and Methods: PyramIDH is a phase 3, multicenter, open-label, randomized, non-comparative study of IVO or AZA monotherapy in patients with HMA-naive mIDH1 MDS. Key eligibility criteria include diagnosis of MDS harboring a locally or centrally confirmed IDH1 R132mutation, ECOG performance status 0–3, and no prior HMA treatment. Patients with any IPSS-Molecular (IPSS-M) risk category other than very-low-risk MDS are eligible. Patients with HR-MDS (including moderate-high-, high-, and very-high-risk categories) are eligible if their bone marrow blast count is below 20%, regardless of blood cell counts. Patients with LR-MDS (including low and moderate-low risk) must have MDS-related cytopenias. Cytopenias are defined as: platelet count <100/μL, absolute neutrophil count <1000/mm3, or hemoglobin <10 g/dL. In addition, patients with LR-MDS must have a blast count between 5% and 19%, and be eligible for HMA treatment.

Approximately 48 patients will be enrolled and randomized (2:1) to IVO or AZA monotherapy, with stratification by IPSS-M risk category (HR vs LR). Patients are treated with 500 mg oral IVO once daily or 75 mg/m2 subcutaneous or intravenous AZA for 7 days in 28-day cycles, until relapse or progression, unacceptable toxicity, undergoing HSCT, death, or other discontinuation criteria are met. The primary endpoint is CR+PR rate at 4 months as per International Working Group (IWG) 2006 criteria. Key secondary endpoints include duration of CR+PR per IWG 2006 criteria, time to CR+PR per IWG 2006 criteria, rate of transfusion independence (TI), rate of transformation to AML, and number of patients bridging to transplant. Other secondary endpoints include CR+PR rate at 4/6 months per IWG 2006 criteria and per IWG 2023 criteria, overall response rate per IWG 2023 criteria, DOR, event-free survival, OS, duration of TI, time to TI, quality-of-life outcomes, pharmacokinetic/pharmacodynamic measures, and safety.

As of July 15, 2025, 34 sites are open for enrollment in 9 countries. In total, 19 patients have been prescreened, 4 have been screened, and 3 patients have been enrolled.

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2025
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