ASH 2023 | Treating transfusion dependent and independent beta-thalassemia, and BELIEVE/BEYOND trial updates

We have to distinguish the two conditions of thalassemia: transfusion-dependent and non-transfusion-dependent. Those transfusion-dependent have a standard of care, which is mainly based on regular transfusion -more or less 2 or 3 units of blood every three weeks and iron chelation to remove the iron accumulated by transfusion. The non-transfusion-dependent thalassemia patients is a definition which includes those thalassemia patients who have quite severe anemia, not requiring a regular transfusion. These patients are able to produce an amount of hemoglobin which allows them to survive without a regular transfusion. They may need occasional transfusions during pregnancy, for example, during infection. But, you know, they may cope with a hemoglobin level around seven or eight. In both cases, the driver of the pathophysiology of the disease is the ineffective erythropoiesis because in beta-thalassemia, which is the form of thalassemia we are mainly focused on, there is a reduced production or even absence of production of the beta-globin chain. So alpha- and beta-globin, which are usually paired to form the hemoglobin, they are unpaired. So, this situation leads to a free alpha globin chain with precipitates within the red cells, causing ineffective erythropoiesis in the bone marrow. In the transfusion-dependent form, we try to reduce or suppress the ineffective erythropoiesis by transfusion. In non-transfusion-dependent, we don’t really manage to control ineffective erythropoiesis. So there is a residual ineffective erythropoiesis which, at the end of the day, is responsible for chronic anemia. So, we may transfuse also these patients with the non-transfusion-dependent to keep their hemoglobin higher and to suppress the ineffective erythropoiesis. But of course, although the standard of care and transfusion made possible a better and longer survival of these patients, it’s still quite a demanding situation. 

Thus, since quite a long time ago, a lot of effort has been put into trying to find a way to control ineffective erythropoiesis. And eventually, one drug was, made available, luspatercept, which has already been approved for the treatment of anemia in transfusion-dependent or thalassemia patients, dating back to 2019 and 2020 for EMA. But more recently, this year it’s been approved also for non-transfusion-dependent thalassemia patients. 

What does luspatercept do? In one case, it is reducing the transfusion burden. In the other case, it is increasing the level of hemoglobin by equal to or more than one gram. So, this was a great success. The two studies, BELIEVE for TDT and BEYOND for NTDT, prompted the registration of the drug and now they are in a long-term follow-up. So, the studies, in both cases, have been completed. And now, for TDT, some data will be presented here at ASH. There is a long-term follow-up, including those patients who were already on luspatercept during the study and those who were allowed to cross over from placebo. 

For TDT, for BELIEVE, there is an extension already of around 230 weeks. And, I should say, that the primary endpoint, which is a reduction of equal or more than 33% of transfusion burden compared to baseline, was maintained in a high proportion of patients. Some actually responded later than during the clinical trial, so I think that the data confirmed that 40% or even more of the patients maintained their response. And, also, those who switched from placebo to luspatercept had a good response. As for the safety, nothing different was observed in this long-term follow up. 

And as for BEYOND, approximately 70% of the patients during the clinical trial achieved an increase of hemoglobin of one or more grams. Actually, we have the same outcome, even the percentage of patients actually achieving a complete transfusion-free time, because these patients, as they say, were not regularly transfused but in the previous observation period, they had some transfusion, and quite a large proportion was completely transfusion-free. Similarly, in terms of safety, nothing was new in the observation. And, in both cases, the results confirm that luspatercept is actually a drug which is targeting ineffective erythropoiesis, definitely useful in thalassemia and maybe also in other conditions. It is already well known for MDS, but it can be considered also for other hemolytic anemias with ineffective erythropoiesis. Now it’s time, with the real-life data, to try to define a profile of responders in order to properly select patients who should be treated with luspatercept without losing time. Is this the solution of everything? This is a great step forward, but still, there is some unmet need because some patients for sure will not be good responders. And for this reason, the scenario of novel treatment of thalassemia is open, with gene therapy, genome editing, and other molecules which are still in clinical trials.