A phase II study of eltrombopag in patients with low-risk MDS and CMML harboring TET2 mutations

Abstract

Abstract Study Rationale. TET2 is one of the most commonly mutated genes in clonal hematopoiesis and myeloid malignancies, including low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Loss-of-function mutations in TET2 disrupt DNA demethylation leading to impaired hematopoietic stem and progenitor cell differentiation. While most current therapies agnostically target cytopenias or disease progression, there remains a critical need for mutation-specific approaches that address the underlying epigenetic dysregulation. We have recently identified Eltrombopag (Epag), an FDA-approved thrombopoietin receptor agonist, as a selective TET2 inhibitor in preclinical models. Epag impairs TET2-mutant (TET2MT) cell growth independently of its thrombopoietic effects and has been shown to reduce TET2MT clonal burden in retrospective analyses of MDS and aplastic anemia patients (pts) by our group. These data supported the clinical investigation of epag as a targeted therapy in TET2MT MDS/CMML. Design. This is an open-label, single-arm, phase II trial (NCT06630221) evaluating the safety, tolerability, and molecular efficacy of eltrombopag in pts with low-risk MDS or CMML harboring TET2 mutations (NCT06630221). Eligible pts are adults (≥18 years) with IPSS-R ≤3.5 MDS or CMML-0 and at least one cytopenia (hemoglobin <10 g/dL, ANC <1.5×10⁹/L, or platelets <100×10⁹/L). Pathogenic or likely pathogenic TET2 mutations must be confirmed by next-generation sequencing. Pts may be transfusion-dependent or independent and must have relapsed or been refractory to prior therapies commonly used in MDS/CMML, including hypomethylating agents, lenalidomide and others. There is no limit on prior lines of therapy. Epag is administered orally, starting at 50 mg daily and titrated to the highest dose of 150 mg daily. Treatment is given for at least 3 cycles; responders may continue for up to 12 additional cycles. Peripheral blood is collected every 3 months; bone marrow biopsies are performed at baseline and end of cycle 3. The primary endpoint is hematologic improvement (HI-P/E/N) at 12 weeks per IWG 2006 criteria. Secondary endpoints include molecular response (reduction in TET2 VAF), AML-free survival, time to progression, and marrow mutation clearance. Exploratory analyses include changes in 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels. The study is designed as a Simon two-stage design that will enroll a maximum of 25 pts. This design will allow for early termination if sufficient efficacy is not observed at the interim look. Stage 1 enrolls 15 patients; if ≥2 respond, an additional 10 pts will be enrolled (N=25). If ≥6 of 25 respond, the regimen will be considered promising. Up to 5 additional patients may be enrolled to offset attrition. Safety analyses include all pts receiving ≥1 dose; efficacy analyses include those with ≥1 response assessment. At Week 12 visit (end of Cycle 3), hematologic improvement will again be assessed. If pts had a clinical response in any lineage at Week 12 but did not yet meet full primary endpoint criteria, EPAG will be continued for 3 cycles and response will be assessed at Week 24. Pts achieving the primary endpoints (i.e., hematologic improvement) at the completion of Week 12 (end of Cycle 3) will continue on the EPAG extension arm for an additional 1 year (12 cycles), or until confirmed progression to AML or high-risk MDS, development of unacceptable toxicity. At the end of the study, the primary endpoint will be evaluated using a proportion and 95% exact CI. Secondary endpoints of AML-free survival and time to progression will be analyzed using the Kaplan-Meier method while reductions in VAF will be evaluated using a non-parametric paired test. This trial is currently open and enrolling across multiple sites within the Cleveland Clinic main campus and affiliated regional institutions. As of August 5, 2025, four pts have been screened, and three have been enrolled. The study is supported by the VeloSano Visionary Award, institutional funding, and drug supply provided by Novartis.