Results from the MEDALIST trial for patients with anaemia in MDS

Bookmark and Share
Published: 1 Dec 2018
Views: 1550
Dr Alan List - Moffitt Cancer Center, Tampa, USA

Dr Alan List gives a press conference at ASH 2018 about the MEDALIST trial, a phase 3 trial using luspatercept to treat anaemia in myelodysplastic syndromes.

Watch his interview with ecancer here.

Read the article about this work here.


Good morning everybody. As you heard, the MEDALIST trial is a randomised phase III study testing luspatercept compared to placebo in a double-blind fashion in patients with lower risk MDS with ring sideroblasts that are transfusion dependent. As a word of background, for patients with lower risk MDS anaemia is the most common symptomatic cytopenia that we deal with and for most of these patients over time the disease becomes transfusion dependent and, with that, comes the attendant complications of iron loading. So recombinant erythropoietins, or what we call the erythroid stimulating agents or ESAs, are the first line therapy that we consider for patients with lower risk MDS, specifically those without deletion 5q. For patients who fail those or are intolerant of those or are unlikely to respond we have a limited number of choices of drugs to offer.

So luspatercept, as you just heard, is a first in class erythroid maturation agent that’s under development for the treatment of patients not only with beta-thalassemia but also MDS associated anaemia. Luspatercept is a soluble receptor chimera that binds to an array of TGF-β superfamily ligands to reduce aberrant Smad 2/3 signalling and, as a consequence of that, enhance late stage erythroid maturation.

In a large phase II study that was done in Europe testing luspatercept in patients with lower risk patients with MDS and symptomatic anaemia, patients with MDS and ring sideroblasts had a higher response rate. That was the rationale for studying that subset of patients in the MEDALIST trial.

As I mentioned, this is a double-blind phase III study. Patients that were eligible for this had to have a diagnosis of MDS with ring sideroblasts defined as either 15% ring sideroblasts in the bone marrow or greater, or having 5% or more ring sideroblasts with an SF3B1 gene mutation. They also had to have lower risk MDS defined by the IPSS revised criteria, including both the very low, low and intermediate risk categories. They also had to be red cell transfusion dependent, receiving at least two units every eight weeks in the sixteen weeks prior to randomisation. They also had to have less than 5% bone marrow blasts. Finally, they had to be refractory to or unresponsive to ESAs or not good candidates for ESAs based upon transfusion dependence in the higher serum erythropoietin level.

Patients were randomised in a two to one fashion to receive luspatercept beginning at a dose of 1mg/kg subcutaneously every 21 days or to placebo. The dose of luspatercept could be escalated during the treatment to as high as 1.75mg/kg every 21 days. The MDS disease assessment was performed as well as response after 24 weeks of treatment and then every six months thereafter. Patients were followed for at least three years after their last dose of treatment for AML progression as well as their subsequent treatment and overall survival.

The primary endpoint for the trial was red blood cell transfusion independence for at least eight weeks or longer within the first 24 weeks of therapy. Some of the key secondary endpoints included red cell transfusion independence greater than 12 weeks in the first 24 weeks and also within the first 48 weeks. Some of the additional secondary endpoints were erythroid hematologic improvement defined according to the international working group criteria of 2006 which includes a reduction in transfusion burden by four units or more every eight weeks in patients that are heavily transfusion dependent or a mean haemoglobin rise of 1.5g/dL over eight weeks.

We had 65 centres that participated enrolling patients between March 2016 and June 2017. As you can see, this included the United States, Canada and centres throughout Europe.

As you can see, there was a greater proportion of patients that achieved red blood cell transfusion independence, the primary endpoint: 58 of 153 receiving luspatercept, or 37.9%, compared to 10 of 76 on placebo, that’s 13.2%. It was highly significant with a p-value of 0.0001. I might point out that patients on the placebo arm that responded had a very low transfusion burden at baseline and they exceeded that eight week threshold from response simply by virtue of changes in transfusion pattern compared to baseline.

For the key secondary endpoints overall 28% of patients on the luspatercept arm achieved red cell transfusion independence for twelve weeks or longer, on the placebo it was six or 7.9% and again that was highly significant. Also overall about 52.9% achieved hematologic improvement, as I mentioned the definition earlier, with luspatercept treatment compared to 11.8% on placebo. I didn’t mention that the median rise in haemoglobin in patients that achieved transfusion independence was 2.55g/dL, reaching as high as 4.1g/dL.

This was a very clean drug and very safe drug; there were no differences in treatment emergent adverse events and absolutely no differences in severe adverse events or the frequency of progression to AML.

So, in conclusion, treatment with luspatercept resulted in a significantly higher proportion of patients who achieved red blood cell transfusion independence compared to placebo as well as erythroid haematologic improvement. It was very well tolerated and those responses were durable with approximately 40% of patients remaining transfusion free after one year of therapy. So luspatercept is a potential new therapy that we think could be very effective in patients with lower risk MDS with ring sideroblasts who are red cell transfusion dependent. Thank you.