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

The purpose of this study is to evaluate if a study drug called eltrombopag can improve the blood cell counts in patients with low-risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) with mutations in TET2 gene, observe changes in the TET2 gene over time, and evaluate the effectiveness of the treatment. TET2 gene is one of the most frequently mutated genes (altered parts of the DNA) in MDS and CMML. Eltrombopag is a Food and Drug Administration (FDA) approved drug for the treatment of severe aplastic anemia and low levels of platelets in patients with persistent or chronic immune thrombocytopenia (ITP) and chronic hepatitis C. Eltrombopag is considered investigational (experimental) in this study because the FDA has not approved its use in the treatment of low-risk MDS or CMML. Eltrombopag is a drug that helps stimulate the body's process of making more platelets (small components of blood that help with clotting) by interacting with specific parts of cells. This interaction starts a series of signals that encourage the growth and development of the cells that produce platelets. It was found that this drug could stop the growth of TET2 mutated cells.

Epigenetic changes such as alterations in DNA methylation and histone modification play an important role in the pathophysiology of myelodysplastic syndromes (MDS). With the development of next-generation sequencing (NGS) platforms, it has become possible to identify genomic aberrations involved in the MDS epigenetics. Additionally, with the advances in therapeutic methods in MDS, several novel genomic aberrations have been reported to predict the effectiveness of specific treatment. It is becoming clear that genomic aberrations may offer more precise cancer phenotypes and help predict precise therapies for MDS patients (e.g. IDH1 and IDH2 inhibitors). TET2 gene is a member of the DNA methylation machinery and one of the most frequently mutated genes in MDS and chronic myelomonocytic leukemia (CMML; a disease entity similar to MDS with similar bone marrow dysplasia and accompanying cytopenias). TET DNA dioxygenases hydroxylate 5-methylcytosine (5mC) to 5-hydroxy-mC (5hmC), a process that leads to passive demethylation and thereby initiation of differentiation programs of hematopoietic stem cells (HSCs). TET2 mutations (TET2MT) often act as founder lesions for clonal hematopoiesis of indeterminate potential (CHIP). Our group has demonstrated that mutational exclusivity of TET2 and isocitrate dehydrogenases 1 and 2 (IDH1/2) result from production of a neomorphic natural TET2 inhibitor α-hydroxyglutarate (2HG). 2HG is selectively and synthetically lethal to TET2-deficient HSCs reliant for their survival on minimal residual dioxygenase activity supplied by less abundant TET1 and TET3. This observation inspired the idea of generating TET inhibitors as drugs selective for TET2 mutant (TET2MT) leukemia cells. Based on the structure of 2HG, investigator generated a more potent TETi76, and showed that this drug is indeed synthetically lethal to TET2MT and TET2 proficient cells. In search for alternative agents with suitable activity, investigator next performed a high throughput drug screen using an in vitro DNA dioxygenase assay. Among several hits, eltrombopag (EPAG) was unique, as it is already used in clinical practice as a thrombopoietin receptor (TPOR) agonist. Investigator showed that this agent inhibited growth of TET2MT cells in murine TET2MT models independent of its TPOR activity, and have determined its binding site and mode of action on TET dioxygenases.1 Since EPAG is an FDA approved drug with known toxicities and good tolerability, repurposing this agent as a TET inhibitor would greatly shorten the development time and thus rapidly provide a selective and well-tolerated drug for the therapy of patients with TET2MT MDS. Investigators have obtained granular molecular and response data from historical trials of EPAG/5Azacytidine in unselected MDS and aplastic anemia (AA) and were able to retrospectively assert that indeed those with TET2MT disease responded to EPAG therapy, resulting in decreased TET2MT clonal burden.