Trial Updates on Low-Dose Lenalidomide and Luspatercept


An overview of updates from the Sintra-REV trial of low-dose lenalidomide, and data from COMMANDS, MEDALIST, and real-world studies on luspatercept.


Rami Komrokji, MD: In terms of approved, available drugs, there are 2 interesting sets of data. One is the update on the lenalidomide and del(5q) from a study conducted by a Spanish group. It’s called SINTRA-REV. Lenalidomide is approved for del(5q) transfusion-dependent patients. They took patients who are anemic and not transfusion independent and randomized them to observation until they become transfusion dependent. They were given a lower dose of the lenalidomide, 5 mg, for only 2 years. Then they stopped the treatment. They presented before the data, but this was the final result.

The time to transfusion dependency, or transfusion-free survival, was way longer with the lenalidomide low dose for 2 years—approaching 6 to 7 years—and the hematologic improvement was almost 77%. Eighty to ninety percent of those patients achieved cytogenetic responses. Obviously, the clonal evolution of the disease is a concern. A subset of those patients had the TP53 mutation, which is commonly enriched in del(5q) patients, but there was no signal of expansion of those TP53 clones. They decreased in many patients, while they stayed stable or expanded in patients not treated.

This could be practice changing. It makes me think of using lenalidomide earlier on…. Maybe you could get a couple of years of treatment and then stop treatment for patients with del(5q). As you alluded to, luspatercept is approved for patients with ring sideroblasts and transfusion-dependent anemia. We have the COMMANDS study, which finished recently, randomizing patients between erythroid-stimulating agents and luspatercept in all comers, who are lower risk and transfusion dependent. We don’t have data. We have a press release that the study is positive. That may change how we use the drug.

At ASH [American Society of Hematology Annual Meeting], there were updates from the MEDALIST study showing that responders had better overall survival and that responses are dose dependent. Especially in patients with a high transfusion burden, we need higher dosing. There were 2 or 3 real-world data subsets presented showing or confirming what’s observed in the MEDALIST study.

Our group presented a proof of principle that luspatercept works on the terminal erythroid differentiation or maturation, and therefore it works on early stage. We looked at the potential combination in a small number of patients. For patients who had primary or secondary luspatercept failure, we added erythropoietin-stimulating agents [ESAs], even though those patients had a prior ESA. Indeed, 30% or more of the patients gained back the response, more in patients who had an initial response to luspatercept and who failed to respond, who had a lower serum EPO [erythropoietin] level, and who had SF3B1 and lower transfusion burden. There’s a proof-of-principle study ongoing in Europe that randomizes patients between luspatercept and luspatercept-EPO. Those things caught my attention. Would you like to comment on those a little or add more? What’s your take on those studies?

Amer Zeidan, MBBS: I agree with you. Those 3 studies show 3 big themes on luspatercept, imetelstat, and early use of lenalidomide. I was impressed with the study looking at lenalidomide because that’s not only the activity of the drug but also the different thinking. Traditionally, we’ve thought about lower-risk MDS as a disease that you don’t intervene with the patient until they’re transfusion dependent. We always struggle with this question because our patients would understandably ask, “If I have this disease, why should I wait until I have significant need for transfusions and not interfere now?” We always want drugs that can potentially change the natural history of the disease. This study was a step in the right direction. As we get more active drugs, we’re going to go more in that direction of looking toward earlier lines of therapy.

Transcript edited for clarity.

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