Hi, everyone. My name is Amer Zeidan from Yale University. I’m here in Marseille at the MDS Foundation meeting. And it’s a pleasure to be with Doctor Valeria Santini from University of Florence to talk a little bit about what’s happening in the meeting. Hi, Valeria.

Hi, Amer.

So I think you’re giving a talk in the meeting about management of anemia in lower risk MDS. Can you give us some sense of the main aspects in your talk that you covered?

Yes, indeed. So, you know, anemia is our main problem with low risk MDS and MDS in general. So, anemia is present in the majority of our patients and symptoms and also the outcome of the disease depends on anemia. So we really need to find a way to treat them. And what I will try to convey in my talk would be the fact that we need to improve even the approach with ESAs – with erythropoiesis‐stimulating agents – because we can improve the rate of response for that old fashioned agents. Then all our patients, almost all of them will lose response to ESAs and again, either need transfusion or have symptomatic anemia. So this is why we have now several tools and attempts. One of course for MDS with ring sideroblast or SF3B1 mutated ones is Luspatercept. But we also have other possibilities that are coming. One is also with Luspatercept for non SF3B1 mutated MDS. The COMMANDS trial that is going to appear in in the next few days has met the objective of showing a positive effect of the drug in transfusion dependent lower risk MDS. So, so we will have possibly another approach for this patient. These were patients who lost or were not eligible to treatment with ESAs. And I will also review new drugs like roxadustat that has a completely different mechanism of action. It’s a drug that has been approved in Europe and in China and in other far East countries for chronic dialysis and non dialysis patient with chronic renal insufficiency, but also studied in MDS and lower risk MDS where it shows around 38% of transfusion independence and hematological improvement provided that the patients do not have a very high burden of transfusion. So low burden of transfusion, very good response and mainly in non RS cases. And again, what is really an interesting agent is imetelstat. Imetelstat is a telomerase inhibitor that has been studied many years ago in myeloproliferative disease. But now in lower risk MDS with transfusion dependence is apparently very, very active in inducing a long-term transfusion independence accompanied by a decrease in the mutational burden. So, probably in the let’s say in the burden of the disease is possibly disease modifying drug. So, that’s another very important step forward for this anemia, chronic anemia of MDS. We have had other attempts in treating patients with lenalidomide, lenalidomide is of course, approved for Del(5q) MDS, not for the others. Some success with treatment in non Del(5q). Also with the addition of ESA. So the combination of the two drugs seems to be quite active as well. It remains off label though. And luspatercept + ESA is a small study by the Moffitt Cancer Center in Tampa by Doctor Komrokji, it shows as well some activity but not in patients without SF3B1. So it’s going to be, it has to be confirmed, but we actually have the idea that we are attacking the anemia and the biology of anemia from several points and with different agents with different mechanism of action. And this is probably the clue to reach success in this disease.

You know, it’s a very exciting year for lower risk MDS. Two of the trials that you mentioned the COMMANDS and the IMerge are going to be presented in oral talks in ASCO 2023 and there’s a lot of excitement at the same time, things have not gone so well in high risk MDS, at least so far, we are hoping this is going to change in the near future. And yesterday in the keynote presentation or in the opening ceremony of the meeting, Doctor Lionel Ades gave a very nice overview of his kind of thoughts on why we have seen a lot of failure of drugs in high risk. And as he cited a few, I think important issues related to the trial design, things related to the lack of good preclinical models, issues with response criteria and the fact that the academic community seems to be more interested in AML compared to higher risk MDS. So what are your thoughts in his overview, how do you think that things could change?

So we have more active drugs in higher risk MDS. So the talk was very interesting and touching upon all the points you just indicated, I think was very intelligent analysis of our situation. Indeed, a preclinical biological model are AML and we cannot translate AML biology into MDS and especially translated into MDS clinical trial and approach. We have had several failures, many of the randomized combined treatment having HMA as backbone plus several agents that seemed to be promising in Phase II study. And I don’t name them, but all of them practically in the last couple of years or more have been failures. So what means failure they did not show what they had shown in the Phase II, meaning good response rate, overall response rate, but also event free survival and overall survival. And what Doctor Ades showed is that we have several mistakes or different approaches that we should change. First of all, in trying to have good models to have preclinical data, then in choosing mechanisms of action on the basis of that. Then another big problem in interpreting phase three randomized trial is that sometimes the expectation and the statistical evaluations are a little bit too optimistic. So if you set your bar too high to obtain an advantage by the addition of the second drug, you will never reach the objective of the study because it’s too high and overall survival can be heterogeneous also on the basis of the choice and selection of patients. So are we going to base it on IPSS, IPSSR or now mainly on IPSS molecular. So this is really something that we should think upon. And well, we and I have shown that in the same study from Phase II to Phase III, the population that we reckon is the same is in fact different on the basis of IPSS molecular. So, if you include in a study different types of patients, you will not get the same results. So this is something very important to keep in mind. And many more clinical trials are devoted to AML compared to MDS, we should select patients, have smaller group focalization of study, focus on mechanism of action and focus on target therapy for MDS. So we have a long way to go if we want to improve and offer our high risk MDS patients something more solid than what we have now.

Thank you so much. This is an excellent summary. Clearly, we have several exciting Phase III trials in high risk MDS. Looking at Venetoclax, Magrolimab, Sabatolimab and Tamibarotene we’re hoping that the same way 2023 has been a big year for lower risk MDS, we’re hoping 2024 will be a big year for high risk MDS. We also look forward to the additional talks in this meeting which just started yesterday and I think there’s a lot of interesting areas that will be covered during the scientific agenda.

Yes, today was devoted to inflammation and clonal hematopoiesis. And of course, we had top speakers that really refreshed these subjects and we really enjoyed, I really enjoyed a lot the plenary session today.