ASH 2023 | An efficacy sub-analysis from the ACE-536-MF-001 study of luspatercept for MF-related anemia

So, anemia is an incredibly common problem in myelofibrosis. Approximately 40 to 50% of patients will have anemia at the time of diagnosis, and at some point in time, every patient will develop anemia, it’s part of the disease process. And anemia can be multifactorial. It can be a result of JAK inhibitors, it can be a result of just dysfunction within the marrow space,  ineffective erythropoiesis, even inflammatory block. And so we’re approaching anemia in a lot of different ways within the context of myelofibrosis. And one of those ways is using luspatercept. Luspatercept is an active ligand trap that promotes late differentiation of erythroid precursors. It works a little bit differently than, say, some of the ACVR1 inhibitors, works a little bit differently than the erythropoiesis stimulating agents. So it’s definitely complementary to all the other things that we’re doing to treat anemia in myelofibrosis. 

And so the ACE-001 study looked at treating anemia in myelofibrosis, both in patients who were transfusion-dependent and transfusion-independent and patients who are on ruxolitinib and not on ruxolitinib. So if you kind of put it in your mind, it’s almost a 2×2 table of four different cohorts of patients. And what we observed was in that study, responses in all four categories, whether patients were transfusion-dependent or independent, whether they were on ruxolitinib or not on ruxolitinib. And mind you, the study was done in a time before there were large amounts of other JAK inhibitors commercially available, so there’s a historical context there. But responses in all groups, the highest response rate was seen in patients who were transfusion-dependent and on ruxolitinib, and so that’s why that cohort was taken forward in the INDEPENDENCE trial. But nonetheless, it is an active agent in all situations in myelofibrosis, and again, really does so by pushing that late differentiation of erythroid precursors. 

You know, the original trial design really focused in heavily on, on a very stringent definition of anemia response, and when we kind of lax that off and use a more practical response, you know, I think the response rates are quite impressive. The very stringent response rates include any reason for anemia at any point in time, which is pretty tough, right? So we had a patient have surgery, and they had some blood loss due to surgery, and that counted as a treatment failure. So, you know, I think it is a good lesson in trying to craft very smart, if you will, endpoints to measure because if you don’t measure correctly, you’re not going to get the answer that you’re looking for. You don’t want to augment the answers either in a favorable manner, but you want to be kind of truthful to the real-world application of these medications. 

You know, this additional dive also looked at ongoing safety events, looking for, you know, anything that might be a red flag for using luspatercept, and really, there were no new safety signals seen with this ongoing analysis. So this is a push now to get this study published and in the peer-reviewed literature, which is the important next step of getting the information out to help support the use of luspatercept, where it’s commercially available here in the United States, and hopefully support overarching evidence as it goes for indications elsewhere.