Eltrombopag treatment for low-risk MDS and CMML with TET2 mutations

A Phase II Study of Eltrombopag as a Novel Therapeutic Approach for Patients With Low-risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) With TET2 Mutations

This trial will try eltrombopag to see if it improves blood counts in adults with low-risk MDS or CMML who have TET2 mutations and have not had adequate responses to prior therapies.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Case Comprehensive Cancer Center (Academic / other)
• Locations: 1 site (Cleveland, Ohio)
• Trial ID: NCT06630221 on ClinicalTrials.gov

What this trial studies

This Phase 2 interventional trial gives eltrombopag to adults with very low-, low-, or intermediate-risk MDS (IPSS-R < 3.5) or CMML-0 who carry a TET2 mutation and have persistent cytopenias despite prior approved therapies. Key eligibility includes a TET2 mutation present at >5%, specific thresholds for hemoglobin, ANC, or platelets, ECOG 0-2, and adequate organ function. Participants receive eltrombopag with regular monitoring of blood counts, safety labs, and serial genomic testing to track changes in TET2 mutation burden over time. The main goals are to document hematologic responses and safety signals in this molecularly defined patient group.

Who should consider this trial

Good fit: Adults (≥18) with very low/low/intermediate-risk MDS (IPSS-R <3.5) or CMML-0 who have a TET2 mutation >5%, meet defined cytopenia thresholds, have ECOG 0–2, adequate organ function, and have failed or been intolerant to prior standard MDS therapies.

Not a fit: Patients without a TET2 mutation, with higher-risk MDS/greater blast counts, or with active severe organ dysfunction are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the treatment could raise blood counts and reduce transfusion needs or cytopenia-related complications for patients with TET2-mutant low-risk MDS or CMML.

How similar studies have performed: Eltrombopag is approved and effective for aplastic anemia and ITP and small, early MDS studies have shown mixed hematologic signals, making a TET2-targeted approach relatively novel but biologically plausible.

Eligibility criteria

Inclusion Criteria:

* Age ≥ 18 years at the time of signing the informed consent form.
* Willing and able to adhere to the study visit schedule and other protocol requirements.
* Established diagnosis of very low-, low-, or intermediate-risk MDS (IPSS-R \< 3.5) and \< 5% myeloblasts or CMML 0 (CMML-0, for cases with \< 2% blasts in PB and \< 5% blasts in bone marrow (BM)z,\[14\] with any one of the notable cytopenias as defined below:

  1. Hgb \< 10 g/dL prior to enrollment
  2. ANC \< 1.5×10\^9/L
  3. Platelets \< 100×10\^9/L
* Must be relapsed, refractory/resistant, intolerant, or have inadequate response to therapies with known clinical benefits for MDS, such as EPOs, luspatercept, and HMAs (i.e., azacytidine or decitabine). Patients with del (5q) must have failed prior lenalidomide therapy.
* TET2 mutation performed at a frequency of at least \> 5%.
* ECOG performance status of 0-2.
* Adequate organ function, defined as:

  1. Serum total bilirubin \< 2x ULN, unless the subject has Gilbert's syndrome. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis. In these cases, approval from the study PI is required.
  2. Creatinine clearance greater than 30 mL/min based on the Cockroft-Gault glomerular filtration rate estimation.
  3. Participants being enrolled on study on the basis of anemia, will only be eligible if folate, B12, serum iron, serum ferritin, total iron binding capacity, haptoglobin and peripheral smear within normal limits
  4. Hepatitis panel negative for Hep B and Hep C infection
  5. Negative for HIV infection
* Women of childbearing potential (WOCBP) may participate provided they have a negative serum pregnancy test at screening and a negative serum or urine pregnancy test within 72 h of starting treatment.
* WOCBP and males with partners who are WOCBP must agree to abstain from sexual intercourse or use effective contraception (methods that result in \< 1% pregnancy rates) during eltrombopag therapy and for at least 7 days after the last eltrombopag dose. Males with partners who are WOCBP must agree to use a barrier method.

Exclusion Criteria:

* High- and Very High-risk MDS (per IPSS-R)
* CMML 1-2
* Prior HMA exposure
* Platelet count \> 200×10\^9/uL or leukocytosis of at least 25×10⁹/L
* Marrow fibrosis (any grade)
* Results of bone marrow biopsy within 1 month of study entry (screening bone marrow biopsy) indicating high-risk MDS or CMML-2.
* Elevated LFTs (aminotransferases and bilirubin) \> 2x ULN
* Pre-existing cardiovascular disease (e.g., known coronary artery disease with percutaneous intervention or stroke within the last year) or arrhythmia (e.g., atrial fibrillation) associated with an increased risk of thromboembolic events, unless deemed acceptable by the enrolling treating physician.
* History of arterial or venous thromboembolism, and on anticoagulation.
* Severe hepatic impairment (Child-Pugh Class C)
* Recent history of cancer (i.e., within the past 5 years) with \> 50% chance of cancer recurrence in the next 5 years
* Current or prior history of hematologic malignancy
* Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
* Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.)
* Positive direct Coombs test
* Evidence of hypersplenism on physical exam
* Pregnant or lactating (women)

Where this trial is running

Cleveland, Ohio

• Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute — Cleveland, Ohio, United States (Recruiting)

Study contacts

• Principal investigator: Abhay Singh, MD, MPH — Case Comprehensive Cancer Center, Cleveland Clinic Taussig Cancer Institute
• Study coordinator: Abhay Singh, MD, MPH

Conditions Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; MDS; CMML