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Professor, Division of Cancer Medicine
Chief, Section of Myelodysplastic Syndromes
Division of Cancer Medicine
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Guillermo Garcia-Manero, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb and Taiho and funds for research support from Bristol-Myers Squibb.
The term “myelodysplastic syndrome” (MDS) refers to diseases of the bone marrow, characterized by what we call “bone marrow failure,” that relate to alterations in the hematopoietic stem cells resulting in either anemia, leukopenia, or thrombocytopenia. During that process, multiple genetic alterations are accumulated that can then influence the progression of this disease, for instance, progression to acute myelogenous leukemia in a subset of these patients or leading to profound dysregulations of the immune system. Generally, MDS is more common in older individuals, but we also see it in younger patients. MDS is extremely heterogeneous in terms of the variety of cytogenetic and molecular alterations, each having distinct clinical and therapeutic implications in terms of prognosis and response to therapy.
Anemia is one of the key clinical hallmarks of MDS, particularly in patients with what is called low‑risk MDS. Low‑risk MDS refers to patients who may have a lower percentage of blasts, more benign cytogenetic type of alterations, and many times, specific genetic mutations that are potentially associated with a more protracted clinical course. But this does not mean that these patients do not need our care. Anemia is one of the major concerns to be managed in this patient population.
Treatment of Anemia With Luspatercept
Luspatercept is an activin-receptor trap first-in-class erythroid maturation agent that binds to molecules that activate TGF‑β signaling in the bone marrow. TGF‑β signaling regulates erythropoiesis, which is dysfunctional in patients with MDS. Luspatercept inhibits ligand binding to TGF‑β with the hypothesis that this will help restore erythropoiesis and improve anemia.
The MEDALIST Trial
In the original phase I/II trials of luspatercept, researchers observed that patients with refractory anemia, ring sideroblasts, and a mutation in SF3B, had a higher response rate to the drug. Researchers launched a number of studies, culminating with the phase III MEDALIST trial, comparing luspatercept vs placebo. Patients on this trial had refractory anemia with ring sideroblasts and had been treated with standard of care erythropoiesis‑stimulating agents (ESA). The MEDALIST study demonstrated that luspatercept improves the rate of transfusion independency, with a good safety profile, in these patients with MDS who are anemic and in need of transfusion. Evidence from this trial resulted in the approval of luspatercept for the treatment of anemia failing ESA treatment and requiring ≥ 2 red blood cell units over 8 weeks in adult patients with very low–risk to intermediate-risk MDS with ring sideroblasts or with MDS/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis.
Using Luspatercept in Your Practice
So the question is: How does luspatercept affect our practice? Although the drug is now approved by the FDA, I think we are in the early phases of its use in practice, where we are still learning when and how to use it. For example, one of my patients has low‑risk disease with a low percentage of blasts and diploid cytogenetics but carries an SF3B1 mutation and has > 15% ring sideroblasts in the bone marrow. That patient had been treated with epoetin alfa or darbepoetin alfa for multiple months and had a high erythropoietin level in the blood but was randomized to the luspatercept arm of the MEDALIST trial. What is interesting about this patient, and I think it is an important point, is that the patient was not very heavily transfusion dependent, meaning that the transfusion burden was low—fewer than 4 units in a 2‑month period. This patient had a spectacular response to luspatercept that was sustained for multiple months.
What we have also seen from the MEDALIST trial is that the toxicity profile of luspatercept is quite benign. This is not a cytotoxic compound, so we do not expect cytopenias or other major toxicities. Some patients may experience fatigue, in most cases mild or moderate (all grades, 26.8%; grade 3/4, 4.6%). Of utmost importance, we have not seen increased progression to acute myelogenous leukemia; such progression would be highly concerning with any intervention in low‑risk disease.
The future for luspatercept is just beginning. The COMMANDS study is a phase III clinical trial comparing luspatercept with standard-of-care ESA in ESA-naive patients with very low–risk, low-risk, or intermediate-risk MDS who require transfusions (NCT03682536). This study is currently enrolling patients, and it will be very important if it proves luspatercept superiority to ESA. Other studies are considering different combinations of luspatercept with other drugs that stimulate erythropoiesis, such as lenalidomide, erythroid growth factors, and perhaps more classic hypomethylating agents. This is all quite promising. In time, I see luspatercept having a potential role in combinations in high‑risk MDS and even in acute myelogenous leukemia, helping clinicians restore erythropoiesis and improve anemia in our patients.
What are your thoughts and questions on using luspatercept in your practice for patients with MDS and anemia? I encourage you to answer the polling question and join the conversation in the discussion box below.