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Advances in MDS
Advances in Understanding Myelodysplastic Syndromes and Individualizing Treatment

Released: August 29, 2023

Michael Savona
Michael Savona, MD
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Key Takeaways
  • Recent approvals of decitabine/cedazuridine and luspatercept have provided new options for the treatment of low-risk and intermediate- or high-risk MDS.
  • Imetelstat, a potentially disease-modifying agent, has been submitted to the FDA for review.
  • Continued research into how clonal hematopoiesis gives rise to MDS may provide the basis for novel therapies.
  • With many new and emerging agents, it is essential that we carefully consider each patient’s presentation and circumstances to better individualize treatment for MDS.

There have been exciting advances in the treatment of myelodysplastic syndromes (MDS), with the development of more new therapies for MDS in the past 2-3 years than in the past few decades. However, challenges still exist with individualizing treatment and reducing disparities in care.

Current Treatment Options
In the past 3 years, the FDA has approved 2 new treatments for MDS—decitabine/cedazuridine and luspatercept. Hypomethylating agents (HMAs) such as azacitidine and decitabine are the backbone of therapies for higher-risk MDS. The FDA approved the combination of decitabine and cedazuridine for adult patients with MDS. The combination provides an oral alternative to injectable decitabine; the cedazuridine component inhibits degradation of decitabine in the gastrointestinal tract. Decitabine and cedazuridine have activity in the treatment of higher-risk disease such as TP53‑mutated MDS or chronic myelomonocytic leukemia. The potential of this drug to improve both ease of treatment and disease outcome is very exciting.

In 2020, the FDA also approved luspatercept for anemia failing an erythropoiesis stimulating agent (ESA) and requiring 2 or more red blood cell units in 8 weeks in adult patients with very low‒ to intermediate-risk MDS with ring sideroblasts or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Patients who do not respond to ESAs may not have anemia severe enough to require transfusions, so having an alternative treatment for anemia is very promising. Luspatercept is a TGF‑β ligand trap that suppresses the negative regulators of late‑stage erythropoiesis, thereby enabling erythroid maturation and improving quality of life for patients with anemia. The phase III COMMANDS trial compared luspatercept with ESAs in patients with very low‒, low-, or intermediate-risk MDS and demonstrated a higher rate of red blood cell transfusion independence with luspatercept. Most recently, the FDA approved a new indication for luspatercept based on the COMMANDS trial. It is now approved for anemia without previous ESA use, in adults with very low- to intermediate-risk MDS who may require regular transfusions.

Imetelstat is another drug that I predict will be approved in 2024 based on results of the recently presented phase III IMerge trial. Imetelstat has a unique mechanism of action in inhibiting telomerase by binding to the RNA template of human telomerase. Telomerase inhibition prevents the continued proliferation of malignant cells. The phase III IMerge trial enrolled patients with low- or intermediate 1‒risk, transfusion-dependent, non-del(5q) MDS relapsed or refractory to ESAs. Imetelstat achieved a durable transfusion independence vs placebo. Of note, imetelstat appears to be disease modifying based on a reduction in variant allele frequency.

Together, these advances allow us more options for patients who do not respond to conventional treatments and represent vast improvements in the treatment landscape.

Opportunities and Challenges in MDS Therapy
The revolution of molecular medicine is a bit like Pandora’s box. Next-generation sequencing is now the standard of care in MDS clinics. As a result, more patterns of mutations are emerging that provide insight into the mechanistic underpinning of MDS. As we learn more about how these mutations provide advantages to cancer cells and how we might be able to perturb that, this will inform a whole new set of therapeutic opportunities, many of them focusing on inflammation. MDS is a very inflammatory state and often starts with mutations in genes that lead to a progrowth, proinflammatory environment in the bone marrow, such as DNMT3A or SF3B1. Such mutations lead to increased inflammation and early cell death through pyroptosis or necroptosis rather than apoptosis. With necroptotic death, there is an increased risk of danger-associated molecular patterns and inflammatory cytokines in the marrow, contributing to a mutagenic, inflammatory environment and causing more inflammation until, ultimately, an accumulation of genetic change leads to bone marrow cancer such as acute leukemia or myelodysplastic/myeloproliferative neoplasms.

MDS experts now have more tools at our disposal and more opportunities to individualize treatment, but it also can be challenging for physicians because the question is no longer simply whether to give an HMA for higher-risk disease. The questions now are: Do we use those drugs at all? Do we use something else instead? Are there disease‑modifying opportunities? Most of the drugs available, such as erythropoietin or luspatercept, are not disease modifying, but they improve quality of life and can lead to hematologic improvement. Decitabine/cedazuridine and azacitidine/cedazuridine change the natural history of disease and are pharmacologic equivalents to the parenteral HMA. As noted above, treatment with imetelstat may be disease modifying based on an association with reduced variant allele frequencies. Investigational approaches for patients with higher-risk MDS have included combining HMAs with other agents, including venetoclax or sabatolimab. Other agents with unique mechanisms of action under investigation for higher-risk MDS include enasidenib (IDH2 protein inhibitor), eltanexor (nuclear export inhibitor), emavusertib (IL-1 receptor‒associated kinase 4 inhibitor), and tamibarotene (retinoic acid receptor a agonist).

Understanding the Molecular Underpinnings of MDS: Clonal Hematopoiesis
I think the most important development in our field is the concept of clonal hematopoiesis (CH) and the age‑associated acquisition of new mutations that may provide a proliferative advantage. The failure to fix these mutations can lead to the expansion of cell lineages, resulting in CH and an increased risk of blood cancer and cardiovascular disease. Of note, the 45-50 genes mutated in 95% to 98% of MDS cases often are seen in CH, yet the epidemiology is different. For example, SF3B1 is the most common mutation in MDS, whereas in CH, DNMT3A is most common. This implies that most patients with DNMT3A do not necessarily develop MDS. Understanding the differences between CH, low‑risk and high‑risk MDS, and acute myeloid leukemia can help us determine which of these CH mutations leads to disease and how we can intervene to prevent it. Many of these genes contribute to inflammation, as noted above, and anti‑inflammatory treatments may be an option to further individualize treatment.

Germline Context
Another component is understanding the contribution of germline mutations in the evolution of CH to MDS. CH does not always lead to disease. Germline mutations in genes such as CHK2, DDX41, RUNX1, and ANKRD26 all predispose patients to developing MDS and acute myeloid leukemia. Conservatively, it is estimated that at least 10% of leukemias are influenced by germline mutations. I think that understanding the context of these germline mutations is the crux of current MDS research and will lead to the next big leaps forward in therapy.

Barriers to Treatment
There is still much to accomplish with respect to making these therapies available to all patients. I practice in Tennessee and see patients from downtown Nashville who have the means to get into the clinic, but I also see patients who live 4-6 hours away—and 30 minutes from medical care of any kind—and may not have the means to come into the clinic regularly. This disparity is important when we think about therapies that require close monitoring or administration in the clinic, such as infusion therapies. To this end, oral HMAs provide us with an opportunity to offer treatment to people who cannot frequently travel. However, these agents have a high copay that many patients cannot afford. We need to narrow the gap between those who have access to medications and those who do not. In addition to improving access to FDA-approved treatments, we must work to ensure that clinical trials are available to all patients in different parts of the country. It is necessary to continue improving upon current therapeutic options by participating in clinical research and offering these clinical research opportunities to our patients. Community engagement is also a critical factor in reducing healthcare disparity. In my region, we deal with high levels of poverty in both rural and urban settings. We adopt a multifactorial approach to address educational differences, cultural sensitivities, and practical issues such as securing transportation and time off work to come into the clinic. It is important that the entire team of healthcare professionals works together to improve equitable healthcare for all.

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