Eltrombopag as a Novel Therapeutic Approach for Low-risk MDS and CMML With TET2 Mutations

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 protocolrequirements.

• 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 definedbelow:

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 totherapies with known clinical benefits for MDS, such as EPOs, luspatercept, and HMAs (i.e., azacytidine or decitabine). Patients with del (5q) must have failed priorlenalidomide 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 ineffectiveerythropoiesis. In these cases, approval from the study PI is required.

2. Creatinine clearance greater than 30 mL/min based on the Cockroft-Gaultglomerular filtration rate estimation.

3. Participants being enrolled on study on the basis of anemia, will only beeligible if folate, B12, serum iron, serum ferritin, total iron bindingcapacity, 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 anegative serum pregnancy test at screening and a negative serum or urine pregnancytest within 72 h of starting treatment.

• WOCBP and males with partners who are WOCBP must agree to abstain from sexualintercourse or use effective contraception (methods that result in < 1% pregnancyrates) during eltrombopag therapy and for at least 7 days after the last eltrombopagdose. 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 marrowbiopsy) indicating high-risk MDS or CMML-2.

• Elevated LFTs (aminotransferases and bilirubin) > 2x ULN

• Pre-existing cardiovascular disease (e.g., known coronary artery disease withpercutaneous 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 cancerrecurrence in the next 5 years

• Current or prior history of hematologic malignancy

• Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limitthe ingestion or gastrointestinal absorption of drugs administered orally.

• Active uncontrolled systemic fungal, bacterial, or viral infection (defined asongoing signs/symptoms related to the infection without improvement despiteappropriate antibiotics, antiviral therapy, and/or other treatment.)

• Positive direct Coombs test

• Evidence of hypersplenism on physical exam

• Pregnant or lactating (women)