Paper Details

ABSTRACT

Background and Significance:

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal myeloid disorders characterized by clonal expansion of hematopoietic stem cells, ineffective hematopoiesis, and a variable risk of progression to acute myeloid leukemia (AML). DNA-methyltransferase inhibitor (DNMTi) monotherapy currently represents the standard of care in higher-risk (HR) MDS with median overall survival (OS) of approximately 2 years across prospective clinical trials, complete remission (CR) rates of 15-20%, and a modest impact on the natural history of the disease.

IDH2 mutations are seen in 5-7% of patients with MDS with increasing frequency noted in higher-risk disease. In addition, median OS is similar in patients with IDH2-mutated (IDH2^mut) MDS in comparison to those with IDH2 wild-type MDS in the era of DNMTi therapy. Enasidenib is a first-in-class oral small-molecule inhibitor of the IDH2-mutant enzyme and is FDA-approved for use in relapsed/refractory AML. Enasidenib has been studied as monotherapy and in combination with DNMTi across several non-randomized early-phase MDS studies with encouraging response rates.

These data led to the development of a myeloMATCH (Myeloid Malignancies Molecular Analysis for Therapy Choice) substudy investigating the oral DNMTi ASTX727 with or without enasidenib in patients with DNMTI-naïve HR IDH2^mutMDS.

Study Design and Methods:

myeloMATCH is a National Cancer Institute (NCI)–led precision medicine platform trial that uses rapid genomic profiling to match patients with newly diagnosed AML or MDS to biomarker-driven treatment substudies. Subjects are enrolled onto the myeloMATCH Master Screening and Reassessment Protocol (NCT05564390) and are then assigned to MM1MDS-A01 (NCT06577441) based on the presence of an IDH2 mutation by NCI myeloid panel testing and a diagnosis of HR MDS.

MM1MDS-A01 is a randomized phase 2 trial enrolling adult patients with DNMTI-naïve IDH2-mutated HR MDS, defined as an Revised International Prognostic Scoring System

(IPSS-R) score of ≥4. Previous treatment with growth factors or luspatercept is allowed and patients with therapy-related MDS are also eligible. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 is also required. Patients are randomized in a 1:1 fashion with stratification factors of IPSS-R score of 4-6 versus >6 and age < 65 vs ≥ 65 years. The control arm is cedazuridine-decitabine (ASTX727) monotherapy (35mg-100mg given day 1-5 of each cycle) and the investigational arm is ASTX727 + enasidenib (100mg daily). A cycle is defined as 28 days. Response assessment will occur at the end of cycles 2, 4, and 6 and every 3 cycles thereafter. Response is defined by the revised International Working Group (IWG) 2023 criteria (Zeidan et al., Blood 2023).

The primary endpoint of the study is CR rate within the first 4 cycles of treatment. The null hypothesis is a CR rate with DNMTi monotherapy (ASTX727) in HR MDS of15%. The alternative hypothesis is that the CR rate will be 45% in the ASTX727 + enasidenib investigational arm. The investigational arm will be compared to the control arm with power = 80% and an overall alpha of 0.05 (one-sided). Given these assumptions, we will enroll 27 patients per treatment arm for a total of 54 patients. A futility analysis will be performed after 28 patients are enrolled.

Secondary endpoints include assessment of event-free survival, OS, toxicity profile, time to response, duration of response, change in IDH2 variant allele frequency, rate of allogeneic transplant, and measurable residual disease (MRD) kinetics by flow cytometry and next generation sequencing.

Of note, patients enrolled to the ASTX727 monotherapy arm are eligible for crossover to receive ASTX727 + enasidenib if a CR, CR with limited count recovery, or CR with partial count recovery is not achieved by the end of cycle 6.

MM1MDS-A01 is a multisite, pan-NCTN study led by the Alliance for Clinical Trials in Oncology that activated in April 2025 and is anticipated to enroll patients through April 2028. The study is currently enrolling in the United States.

Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org