Eltrombopag for the Treatment of Relapsed or Refractory Very Low, Low, or Intermediate Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia-0 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 protocol requirements
• Established diagnosis of very low-, low-, or intermediate-risk MDS (Revised International Prognostic Scoring System [IPSS-R] ≤ 3.5) and ≤ 5% myeloblasts or CMML 0 (per World Health Organization [WHO] 16), with any one of the notable cytopenias as defined below: * Hemoglobin (Hgb) < 10 g/dL prior to enrollment * Absolute neutrophil count (ANC) < 1.5 x 10^9/L * Platelets < 100 x 10^9/L Qualifying cytopenias, as defined above, must be documented either within the 6 months before screening or during the 28-day screening period
• Must be relapsed, refractory/resistant, intolerant, or have inadequate response to therapies with known clinical benefits for MDS, such as epoetin alphas (EPO)s, luspatercept, and hypomethylating agents (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%
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Serum total bilirubin < 2 x upper limit of normal (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 principal investigator (PI) is required
• Creatinine clearance greater than 30 mL/min based on the Cockroft-Gault glomerular filtration rate estimation
• Patients being enrolled on study on the basis of anemia, will only be eligible if folate, vitamin B12, serum iron, serum ferritin, total iron binding capacity, haptoglobin, and peripheral smear are within acceptable limits. If B12, folate, or serum iron levels are low, this may indicate nutritional deficiencies. Similarly, a haptoglobin level below 10 or the presence of schistocytes on peripheral smear may suggest alternative causes of anemia. These findings do not disqualify patients from study participation but will require further evaluation by the treating hematologist, anemia clinic or classical hematology team prior to enrollment
• Hepatitis panel negative for hepatitis (Hep) B and Hep C infection
• 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 hours (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
• We will utilize the 2016 World Health Organization (WHO) criteria for the diagnosis and staging of chronic myelomonocytic leukemia (CMML) Diagnostic Criteria for CMML (WHO 2016): * Persistent peripheral blood monocytosis (≥ 1 × 10^⁹/L), with monocytes accounting for ≥ 10% of the white blood cell count * Exclusion of BCR-ABL1 positive chronic myeloid leukemia (CML), primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) * No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2 (especially in cases with eosinophilia) * Less than 20% blasts (including promonocytes) in the peripheral blood and bone marrow * Dysplasia in one or more myeloid lineages. If myelodysplasia is absent or minimal, CMML diagnosis can be made if: ** An acquired clonal cytogenetic or molecular genetic abnormality is present in hematopoietic cells, or ** Monocytosis (as previously defined) has persisted for at least 3 months and all other causes of monocytosis have been excluded CMML Staging (WHO 2016): * Stage: CMML-0; Peripheral blood blasts: < 2%; Bone marrow blasts: < 5% ** CMML-1: Blasts <5% in peripheral blood and <10% in bone marrow will be excluded ** CMML-2: Blasts 5–19% in peripheral blood or 10–19% in bone marrow, or presence of Auer rods will be excluded These criteria and stages will be used throughout the study for patient inclusion, stratification, and analysis

Exclusion Criteria

• High- and very high-risk MDS (per IPSS-R)
• CMML 1-2
• Platelet count > 200 x 10^9/uL or leukocytosis of at least 25 x 10^9/L
• Marrow fibrosis * Since stromal (reticulin) fibrosis can be reactive and reversible, while collagenous fibrosis is more strongly associated with adverse outcomes and is less likely to resolve with therapy, only cases with evidence of collagenous bone marrow fibrosis will be excluded from the study. Thiswill ensure that exclusion is based on the more compelling and prognostically significant form of fibrosis, rather than on potentially reversible or reactive stromal changes
• Results of bone marrow biopsy within 1 month of study entry (screening bone marrow biopsy) indicating high-risk MDS or CMML 1-2
• Elevated liver function tests (LFTs) (aminotransferases and bilirubin) > 2 x 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 * A concomitant cancer that is early stage and well controlled, and managed exclusively with hormone therapy such as aromatase inhibitors (AIs) or selective estrogen receptor modulators (SERMs) for breast cancer, or androgen deprivation therapy (ADT) for prostate cancer, with an expected life expectancy greater than 5 years from the early stage cancer, may be eligible for enrollment in this trial
• 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)
• Unable or unwilling to discontinue prior anticancer therapy. The use of intercurrent anticancer therapy (standard care or investigational) is not permitted. Any use of prior anticancer therapy is to be discontinued at least 14 days prior to cycle 1 day 1 (or longer depending on drug elimination properties). Note: the use of steroids for short terms intervals (≤ 14 days) or reasons not related to cancer therapy (e.g., topical, ocular, pulmonary, etc. purposes) is NOT exclusionary
• For eligibility, in addition to above mentioned therapies, patients may have received prior MDS-directed therapies, including but not limited to thrombopoietin receptor agonists (romiplostim) for severe or refractory thrombocytopenia that is MDS-related, immunosuppressive therapy (± thrombopoietin [TPO] agent) as per National Comprehensive Cancer Network (NCCN) guidelines, and other supportive interventions. For CMML patients for eligibility, prior use of hydroxyurea, JAK inhibitors, and hypomethylating agents (HMAs) is permitted. The impact of these prior therapies on eligibility and stratification will be considered in accordance with the most recent NCCN recommendations and published clinical evidence