Harry P. Erba, MD, PhD: Let’s turn to another class of agents—specifically, luspatercept, which has been studied mostly in MDS [myelodysplastic syndromes] for anemia but potentially has a role in myelofibrosis. We’ll find out. Rami, do you want to tell us about that?

Rami Komrokji, MD: Absolutely. As I alluded to earlier, anemia is a major issue in myelofibrosis, as well. There is a subset of patients where that’s the main issue, the cytopenia, but it’s also seen sometimes with treatment like ruxolitinib. There is a need to treat those patients on limited options. Luspatercept and sotatercept are new novel agents that target [the] TGF [transforming growth factor]—beta pathway that in both diseases—at the beginning, it was tested in MDS, obviously—was demonstrated to be overactivated. Some of those ligands that go through the TGF-beta pathway, like GDF11, seem to be involved in terminal erythroid differentiation. Those drugs, luspatercept or sotatercept, are monoclonal antibodies that are trap fusion proteins. They bind the ligands before binding the receptor.

In MDS, they were tested in phase I and phase II studies showing promising efficacy, particular signals in patients with ring sideroblast or splicing mutation. Luspatercept is the one that moved forward in MDS. There was a phase I/II study and, recently, a phase III study that was a randomized clinical trial called MEDALIST that finished accrual. We don’t have the results from that study. If that study is positive, the drug will be approved in MDS.

Harry P. Erba, MD, PhD: The endpoint would be improvement in anemia?

Rami Komrokji, MD: Right.

Harry P. Erba, MD, PhD: It should be an early readout, not a survival endpoint.

Rami Komrokji, MD: Yes. It’s red blood cell transfusion—independent hematologic improvement. The primary endpoint is transfusion independence. As you mentioned, hopefully, by the end of this year, we will hear something about it. Obviously, the TGF-beta pathway is also known to be overactivated in myelofibrosis, so it makes sense to test it in that disease. I think Srdan’s group already tested sotatercept, which is the first drug we were working on in the United States. Luspatercept was mostly developed in Germany, then came to the States. In a pilot study presented by Srdan’s group, they demonstrated that sotatercept was active in myelofibrosis patients and had responses. Interestingly, all patients were female who responded in that study.

Srdan Verstovsek, MD, PhD: Now we have a few males.

Rami Komrokji, MD: All right, good. Now luspatercept is actually being tested in myelofibrosis in several groups, looking at patients who are on ruxolitinib and have had anemia, patients who are transfusion-dependent or not transfusion-dependent with ruxolitinib, or patients who are not on ruxolitinib, whether they are transfusion-independent or just anemic before transfusion independence. I say anemia is definitely an unmet need in myelofibrosis, and this drug is promising and definitely worth testing by enrolling patients on trial.

In terms of tolerability in the MDS setting, the drug is very well tolerated. It’s given every 3 weeks as subcutaneous injection. No major adverse effects have been reported so far. In the studies, they monitor development of hypertension because historically, erythrocytosis was the dose-limiting toxicity, and they’re testing it in healthy volunteers. There are some myalgias but really no major red flag of toxicity so far.

Harry P. Erba, MD, PhD: Clearly, from the work of Alan List at your institution and others, innate immunity is very important in the pathogenesis of MDS and likely other myeloid neoplasms. But this sounds a little bit like déjà vu all over again. Don’t I remember from 15 years ago looking at etanercept in MDS?

Rami Komrokji, MD: Right, but they looked at a different pathway. It was not looking, really, at the TGF-beta pathway. There have been several attempts, such as looking at drugs targeting the inflammatory pathway, and more recently we looked at several drugs that target the MAP [mitogen-activated protein] kinase, like the trial we did with MD Anderson. There were always small responses. The responses in MDS with luspatercept or sotatercept approach almost 40% unselected. When you look at the patients with ring sideroblast, especially if they are not heavily transfusion-dependent, the responses are in the range of 60%, which really seems very promising. Hopefully, the results of the phase III trial will confirm that.

Transcript Edited for Clarity