Shastri Stresses the Need for Risk Stratification to Personalize Decisions in MDS

Aditi Shastri, MBBS

With more agents designed to induce transfusion independence available for patients with myelodysplastic syndromes (MDS), risk assessments are necessary to better understand prognosis while considering performance status and comorbidities to develop a personalized treatment, according to Aditi Shastri, MD.

“For MDS, it’s very important to risk-stratify the disease so we can tailor the therapy appropriately for patients,” Shastri said. “We have multiple risk-stratification tools… that incorporate various biological variables like bone marrow blasts, karyotype, and whether the patient has any neutropenia, thrombocytopenia, or anemia. This is all important [to know] because it provides us with an idea about patients who have low-risk disease and who have a better median [overall] survival than those with high-risk disease.”

In April 2020, luspatercept-aamt (Reblozyl) received regulatory approval from the FDA for the treatment of anemia failing an erythropoiesis-stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. The decision was based on data from the phase 3 MEDALIST trial (NCT02631070), which showed that 38% of patients who received luspatercept achieved red blood cell transfusion independence for 8 weeks or longer vs 13% of those who received placebo (P <.001).

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on hematologic malignancies, Shastri, an assistant professor in the departments of medicine (oncology) and developmental and molecular biology at Albert Einstein College of Medicine, discussed risk stratification tools, her treatment algorithm for patients with low-risk MDS, and the role of luspatercept in this population.

OncLive^®: What is your current approach for risk stratification in MDS?

Shastri: For MDS, [we need] to risk-stratify the disease to [inform treatment] appropriately. We have multiple tools, like the International Prognostic Scoring System [IPSS] and the revised IPSS. These are tools that were developed more than a decade ago that [provide us with necessary information]. Once we risk-stratify these patients, it’s also very important for us to know a few other [factors].

An important [factor is] performance status. A 70-year-old person who runs a marathon is very different from a 60-year-old person who might have a lot of comorbidities like diabetes or heart disease. Getting a very adequate assessment of their performance status and comorbidities is extremely important so we can offer the patients the right treatment that they can tolerate.

With regard to low-risk MDS, what algorithm do you use to tailor treatment?

When you see a patient with low-risk MDS for the first time, it is important to rule out other causes of anemia. You have to ensure that they don’t have an iron deficiency or a nutritional deficiency, as those are easily correctable. Once we are sure that the patient truly has low-risk MDS, by looking at their peripheral smears, bone marrow biopsies, and checking the karyotype, we risk-stratify them. The approaches depend a little bit on what type of disease the patient has. A subset of patients have a specific karyotype, deletion 5q. Patients who have this particular phenotype and genotype are exquisitely sensitive to lenalidomide [Revlimid], which is an immunomodulator. They have very good erythroid response, as well as remission rates or transfusion independence, while on this particular drug. [For these reasons,] we like to treat [these patients] with this particular agent.

For patients who have MDS with ringed sideroblasts, we now have luspatercept, which is FDA approved. Other drugs that are also used to treat [patients with] MDS are growth factors, such as erythropoiesis-stimulating agents, which can be used if the patient is transfusion dependent and their erythropoietin levels are low.

There’s also hypocellular MDS, which is interesting; it has an overlap with an autoimmune syndrome, such as aplastic anemia. Patients who have hypocellular MDS actually do better when we treat them with a therapy that targets their immune system, so we use immunosuppressive therapy. [If] they progress on this first-line therapy, we can always offer them hypomethylating agents, such as azacitidine and decitabine, on an abbreviated schedule with lower doses; [their use has been] well published.

How do you navigate among the growth factors that are available?

Typically, patients with low-risk MDS need growth factors for red blood cell transfusion dependence. We do have epoetin alfa and darbepoetin alfa that we can offer patients, especially those who have low erythropoietin levels. Data have shown that these drugs, given concurrently with white blood cell growth factors, actually boost response rates. For patients who have anemia, as well as neutropenia, it might be a good strategy to give both of these drugs together. We also have more of an off-label indication [for] eltrombopag [Promacta], which is typically considered to be a thrombopoietin receptor agonist and helps to boost the platelet count. [The agent] has also been shown to improve not just the platelet counts, but the neutropenia and anemia as well.

In April 2020, luspatercept was approved by the FDA based on the results from the phase 3 MEDALIST trial. How are you applying the data from this trial to clinical practice?

It is very encouraging that we now have a new drug for treating this group of patients. That being said, this is a small subset of patients with MDS, so we are a little restricted in [who can receive] this drug. We are primarily using the drug for patients who have specific splicing factor mutations, as well as refractory anemias with ring sideroblasts. These patients have a really nice response. They’re able to get off their transfusions and have a better quality of life. Many ongoing studies are looking at luspatercept across MDS in general or [as part of different] combination strategies. We are awaiting the results of those studies.

Reference

1. US Food and Drug Administration (FDA) approves Reblozyl (luspatercept-aamt), the First and only erythroid maturation agent, to treat anemia in adults with lower-risk myelodysplastic syndromes (MDS). News release. Bristol Myers Squibb. April 3, 2020. Accessed February 11, 2021. https://bit.ly/2JEHtGG