Therapy Options in Low-Risk Myelodysplastic Syndromes


Hetty Carraway, MD: Let’s talk a little bit about the patients with lower-risk MDS [myelodysplastic syndromes]. What kinds of therapies might be available to a patient, particularly if they present with an isolated anemia or low hemoglobin? What should they be asking you or thinking about?

Guillermo Garcia-Manero, MD: Thank you, Hetty. First of all, I think around 60% of patients with MDS will first present in a lower-risk category. What you do first is look at the bone marrow test, of course, but let’s go one by one. The first line of therapy for someone who just has anemia may be a drug that stimulates red blood cell production. We call those agents erythropoiesis-stimulating agents, or ESAs, and there are a couple of them that can be very effective in the correct subset. We measure something in the blood of the patient called the erythropoietin level, and if that’s low, the patient will most likely respond to ESAs. Those drugs are biological agents. They are actually a hormone that we have in our own body, and they help stimulate the bone marrow to produce red cells.

For the low white blood cell count, my experience is that when it’s isolated, patients can do well for a long time and they don’t really have an increased risk of infection. That’s a small subset of patients. What I find more problematic is when the patient presents with low platelets, particularly if they are really low. When it’s below 30,000, you may be in a situation where you have a spontaneous bleed, and that could be fatal. There are no good agents that stimulate these platelets in the bone marrow. Sometimes we use compounds that we use for other disorders, like ITP [immune thrombocytopenic purpura], but they don’t really work for most patients. So we sometimes consider some very low form of chemotherapy, the hypomethylating agents, for patients who may have anemia with very significant low platelets or thrombocytopenia.

There’s a relatively small group of patients where the therapy is very effective. These patients have anemia, but with a particular chromosomal alteration is called 5q minus, or an alteration of chromosome 5. There is an agent called lenalidomide that is extremely effective. It’s an oral agent, has been approved for many years, and can be very effective for a long time in patients with this particular alteration.

This year, we saw the approval of a new drug for patients with myelodysplastic syndrome. This drug, known as luspatercept, was the first drug that got approved in 14 or 15 years. This is a drug that modulates something we call TGF-beta [transforming growth factor-beta], that basically is involved in the generation of these red cells, so it’s effective in patients with anemia. Right now, the drug is used for a specific subset of MDS called refractory anemia with ring sideroblasts with patients who have already been treated with erythropoiesis-stimulating agents. We are also testing that particular drug in an upfront clinical trial as the first drug to be used for patients with anemia.

There are supportive care issues that are critical. Sometimes we consider prophylactic antibiotics for some of these patients. Of course, transfusional support is very important. Now with COVID-19 [coronavirus disease 2019], we have fewer donors, and this is sometimes challenging in our practices. There’s been some controversy in terms of the use of chelation therapy, meaning treatments to remove iron from our patients. But a paper that was published a few months ago suggested that there’s some benefit in terms of survival for some patients who have high iron levels.

And finally, there is a specific subset of patients with we call hypoplastic MDS. These patients sometimes share some features with a related disease called aplastic anemia, and they may benefit from immune therapy with a treatment called ATG [antithymocyte globulin]. This is an immune-based treatment that can be effective in patients with hypoplastic MDS, which resembles aplastic anemia. I’m not sure about the Cleveland Clinic, but some of the groups may use ATG-based therapy in some other subsets of patients that we know may be responsive to this compound. But this is basically the approach. Very rarely do we consider transplant in low-risk disease—the mortality and toxicity is way too high. We may consider a transplant as a second- or third-line approach in younger patients who are not responding or have lost benefit to whatever early therapy we have for lower-risk disease. Hetty, do you do something different or in addition at the Cleveland Clinic?

Hetty Carraway, MD: You gracefully walked through all of the options that are out there when we think about a patient with a lower-risk MDS. Certainly in the upfront setting, much of what we start with is the ESA-based therapy to help reverse or support transfusion dependence in somebody who has low hemoglobin. These therapies are well tolerated. The duration of response for some of these patients can be longer than a year, particularly if they have a low erythropoietin level or low serum erythropoietin level, which is a laboratory value that we check by looking at the blood. Also, if they have a low transfusion burden, those two pieces together help us predict whether somebody has a higher or lower likelihood of responding to ESA-based therapy.

Some of those molecular mutation tests from the NGS [next-generation sequencing] testing can also give us some clue as to whether people are more likely to have a durable response. You alluded to those patients with refractory anemia with ring sideroblasts, and patients who have that particular finding on their bone marrow aspirate more often have a mutation called SF3B1. We’ve learned that those patients respond quite nicely to a new agent that was FDA-approved called luspatercept. This was a pretty exciting thing this year. This is the first time in a long time that we’ve had newer agents approved for patients with MDS, such as luspatercept. I recall when AZA [azacitidine] and decitabine were FDA-approved in 2004, 2006, and we’ve waited a long time for another agent to be approved. That was huge this year. We’re now investigating this agent, luspatercept, in the upfront setting to better understand if this is an agent that we should use before we even consider using ESA-based therapy. I’m eagerly awaiting the results of that study as well.

Transcript Edited for Clarity

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