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Associate Professor of Medicine
Clinical Director of Leukemia Services
Division of Hematology
University of Colorado School of Medicine
Daniel A. Pollyea, MD, MS, has disclosed that he has received consulting fees from AbbVie, Aprea, Astellas, Bristol-Myers Squibb, Celgene, Foghorn, Genentech, Gilead Sciences, Kiadis, Novartis, Syndax, Syros, and Takeda Oncology and funds for research support from AbbVie and Teva.
Myelodysplastic syndrome (MDS) is a very heterogenous disease, and as such, there is a wide variety of treatment approaches. The most important initial assessment after diagnosis is to calculate the prognostic risk by the revised International Prognostic Scoring System (IPSS-R), a measurement incorporating key clinical variables including bone marrow blasts, cytopenias, and cytogenetic risk categorization.
Patients with intermediate to low risk (defined as IPSS-R <4.5) who are asymptomatic and independent of transfusions may be observed without intervention. This typically requires visits and blood count checks 2-4 times per year to monitor for evidence of disease progression. Patients with intermediate-risk to low-risk disease who are symptomatic or who require transfusions can either be treated with an erythropoietin-stimulating agent (epoetin alfa or darbepoetin alfa) if the erythropoietin level is low at baseline or blood or platelet transfusions on an intermittent basis. I favor this approach in patients who are too frail to be considered good candidates for treatment or those who only require minimal transfusions.
If patients require more frequent transfusions or have more symptoms related to their disease, and have failed to respond to an erythroid-stimulating agent (or do not have a low baseline erythropoietin level), we should treat the underlying disease. In the presence of MDS with del(5q) syndrome, lenalidomide is the preferred therapy. In the presence of ring sideroblasts, luspatercept can be considered, although I consider this not so much a treatment for the underlying disease as it is a way to improve hemoglobin levels, so it should only be considered if anemia is the predominant finding. Patients without either of these findings should be treated with a hypomethylating agent (HMA)—either azacitidine or decitabine. Decitabine can be used as an oral therapy or IV, as both are equivalent, and azacitidine can be given IV or subcutaneously, also with equivalent results. The oral formulation of azacitidine, however, is not equivalent and is not approved for use in this setting.
Some patients may not respond after treatment with any of these therapies—or respond and then progress. In some cases, this can result in patients evolving to acute myeloid leukemia or higher-grade MDS (MDS with increased blasts). In these patients, I would recommend an HMA if they did not previously receive one. Patients who continue to progress on one HMA may consider switching to the other if they did not receive it previously. If progression continues after these approaches, there are no other conventional treatment options currently available, and I would encourage enrollment on a clinical trial as the only realistic therapeutic option to pursue.
Patients with higher-risk disease (IPSS-R >4.5) are usually offered systemic therapy, but some patients are considered too frail for these interventions and are offered supportive care, with transfusion support only. For patients suitable for therapy, the first-line treatment recommendation is an HMA. Some patients with high-risk disease who do not have excess blasts may proceed directly to an allogeneic stem cell transplantation, whereas others may receive an HMA prior to transplant. Patients with excess blasts, for example, are typically treated with an HMA prior to transplant or with intensive induction chemotherapy regimens such as 7+3, as they would be treated if they had acute myeloid leukemia. If the patient’s disease fails to respond or responds and relapses, further treatment options are limited and appropriate clinical trials or supportive care only should be considered.
Numerous exciting investigational treatment options are currently being studied for lower-risk and higher-risk MDS, including the anti-CD47 agent magrolimab, the BCL-2 inhibitor venetoclax, and the TP53 mutation–targeting eprenetapopt (APR-246), all in combination with azacitidine. These and other clinical trials for MDS are most welcome, because beyond transplantation, there are currently no curative options for these patients.
What are your most pressing questions regarding MDS management? I encourage you to answer the polling question and join the discussion in the box below.
Also, join me and my colleagues Drs. Amy DeZern and Amer Zeidan for a 1-hour Cancer Conversations Webinar on October 4, 2021, at 3:30 PM ET as we discuss challenging cases, the latest data, and answer your questions in the management of myelodysplastic syndrome!