EHA 2025 | An overview of the current interventions for patients with LR-MDS and anemia

Now finally we have quite a number of options of therapy for patients with lower-risk MDS and anemia. And these options are very different in the sense that we have the usual initial approach in my mind for non-transfusion dependent patients with symptomatic anemia that is ESAs. So these are patients who should receive their treatment very early. And this is independently of the cytogenetic defect. Among patients who then lose response to ESA, that by the way can be extremely long, the ones that lose response may have then an array of options. 

One option is the one we know since a long time for del(5q) patients, that is lenalidomide. Now, there are data coming from the Spanish group suggesting that the sooner you act, so if you start lenalidomide treatment in del(5q) patients who do not have transfusion burden and transfusion needs, you obtain a longer transfusion-free period and a higher response rate, even if you use a lower dose, that is 5 milligrams per day per 21 days. Having said so, if you become transfusion dependent, lose response to ESAs or you cannot be treated with ESAs and you are non-del(5q), the options now are several. 

Now, luspatercept, that is a ligand trap of the ligands for activin receptor 2, is active in patients who are transfusion dependent, low risk, and have never received ESA, so let’s say naive. And this is clearly shown in the percentage of transfusion independence rate achieved after this therapy that is higher than 70%. And compared to EPO, that was the comparison to this treatment, it is a significant advantage. Now, not all countries have the approval of luspatercept in this setting, or better, the approval is there, but the reimbursements are not there. So we are still waiting to be able to use more widely this treatment. Luspatercept is a sub-Q therapy that has to be given at an initial dose of 1 mg per kilogram every three weeks and then escalated up to 1.75 mg per kilogram if the patient is not responsive. ESAs show, in this sense, a lower activity as it is known because the patients who are transfusion dependent do not respond so well to ESAs and more so if they have a high transfusion burden. So, as I say, the recommendation is to start early with ESA and then come to other options when transfusion dependency is established. 

This is for the so-called first line, I would say second after transfusions. For these patients, we may envisage other treatment afterwards, but what I want to say is that if the patient has already received ESA and they become transfusion dependent, then we have luspatercept as well as a second line treatment and imetelstat. So we have a double choice. Luspatercept is extremely active and for a long time in patients who have a slightly less important transfusion burden, whereas imetelstat can be extremely active also in patients who have high transfusion burden because in the IMerge study that brought to the approval of the drug, you had a median of six units of red blood cells in eight weeks. 

Now imetelstat is an IV drug, it is given every four weeks and it has the, let’s say, the problem, it’s a small transient problem, but it gives myelotoxicity. So thrombocytopenia and neutropenia. And this is why these patients have to be monitored for these cytopenias. But overall, as I mentioned before, IMerge showed a significant increase in transfusion independence, nearly to 40%. The patients who achieve this eight-week transfusion independence can, in 70% of cases, have and maintain transfusion independence for six months. What I didn’t mention is that when you use luspatercept before ESA, so when patients are in first line, the study showed an extremely long maintenance of the response, 126 months, meaning that here as well, if you start earlier, compatible with the diagnosis and the referral of the patients, your results are really consistent and are longer and better.

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