Examining Luspatercept Efficacy for Anemia and Transfusion Burden Among Patients With Myelofibrosis

According to data from the ACE-536-MF-001 trial, treatment with luspatercept improved anemia and transfusion burden among patients with myelofibrosis (MF), and demonstrated a safety profile matching that of previous studies, with no new safety signals observed.

Aaron Gerds, MD, Cleveland Clinic Taussig Cancer Institute, Cleveland, California, presents further context and insights into the data and results, as well as explains next steps for investigating luspatercept in further clinical trials.

Transcript:

Hi. My name is Aaron Gerds. I'm Associate Professor of Medicine at the Cleveland Clinic Taussig Cancer Institute and I also serve as the Medical Director for the Case Comprehensive Cancer Center Clinical Research Office.

It's my absolute pleasure to work on this project looking at luspatercept for the treatment of myelofibrosis-associated anemia. Anemia is incredibly common in myelofibrosis. It occurs in anywhere from 30% to 40 % of patients at the time of diagnosis. And, at some point in time, every patient will become anemic over the course of their disease. Anemia comes with feeling tired, worn down, [patients] also may need transfusions to remediate.

And transfusions, of course, come with a whole set of logistical and physical problems as well. And so any therapy we have in myelofibrosis that can improve anemia is warranted, and a welcome addition to our armamentarium. We looked at luspatercept in this phase 2 trial, the ACE001 study. The patients were broken down into 4 groups: those on ruxolitinib (rux) and those not on ruxolitinib, those who were transfusion-independent and those who were transfusion-dependent. In your mind you can come up with a 2 by 2 table of 4 different cohorts. They were named cohort 1, cohort 2, cohort 3a, and cohort 3b, with cohort 3s being those who were transfusion dependent.

If we look at the patients who were included in the study, most had a primary myelofibrosis, quite a few were receiving treatment for some time. So those 2 cohorts that were receiving concurrent ruxolotinib, the median time on ruxolitinib was about 18 months, so quite a bit of treatment leading into that period of time. In terms of disease-risk, most patients were intermediate-1, but nonetheless, 13% of patients were high-risk. In terms of those patients receiving transfusions, those transfusion-dependent patients, at least half were receiving 6 to 12 units every 84 days. So, a very heavily transfused group, for that group of patients.

We looked at adding luspatercept on top of ruxolitinib, and the dosing was very similar to what you may see in the package insert, or what's used for myelodysplastic syndromes (MDS). We started off at a dose of 1 milligram per kilogram given every 3 weeks, and that could escalate depending on response. What we saw is we saw that no matter what the baseline population was, we saw responses in every group. We saw responses in patients who were not on rux and not transfusion-dependent. We saw responses on those who were on rux and those who were also transfusion-dependent. Every cohort had responses.

Our primary end point was a very stringent window response. And if you've ever looked at a trial looking at anemia myelofibrosis, you may scratch your head because these end points are very difficult to follow. But in essence, the primary a priori end point was looking at a defined window of time, and not receiving any transfusions during that period of time, for those who were transfusion-dependent. And for those who were transfusion-independent, it was really a gram and a half increase for the duration of that window.

This is really tricky—say a patient gets an infection, and temporarily their hemoglobin drops, or has a surgery that's unrelated, like an appendectomy, and their hemoglobin drops, then in that window they would be deemed a non-responder. So, very stringent. Despite the stringent end point, we were seeing responses depending on the cohort from anywhere from 10 to almost 30 percent of patients. The subpopulation of patients that did the best, that had the highest number of responses were those who were on rux and who were transfusion-dependent.

Now, if you come up with a more practical end point, say a rolling 12-week period, at any point during therapy, the response rates increase dramatically. If we look at that cohort 3b again, and we say, for any patient who is transfusion-independent for a 12 week period, rolling throughout the evaluation, the response rate jumps up to 50%. So half of patients met that kind of end point, which is a pretty significant chunk of patients. Even in those who weren't transfusion-dependent, we see the response rates much higher with this much more practical end point.

One of the take-homes from this trial was trying to design rational and practical end points for measuring anemia response and myelofibrosis. That was certainly one of the things we learned as a product of this. But ultimately we learned that luspatercept can effectively improve anemia in these patients. Of course, there's no such thing as a free lunch and we want to think about side effects that can occur. The main side effects we saw, which were quite minimal, were headaches and elevated blood pressure, as well as in some patients experience bone pain. Those were the major side effects that we observed throughout the course of the study. 

The phase 2 trial has been accepted for publication in Blood Advances and is moving forward and has been then turned into now a phase 3 trial called the independent study, which is ongoing. The ultimate next steps for luspatercept is getting the results from the independent study, a randomized phase 3 trial looking at patients who are on ruxolitinib who also are transfusion-dependent, that will serve as a basis potentially as a label expansion for luspatercept. I think the other big piece of work that needs to be done is looking at other, combining with other agents.

Ruxolitinib is not known for improving anemia in significant numbers of patients, where we do have now JAK inhibitors that can, both momelotinib and pacritinib, through inhibition of ACVR1. And that inhibition is in parallel to how luspatercept works on anemia, so potentially they could have a synergistic effect. So looking at the combinations of luspatercept plus momelotinib, luspatercept plus pacritinib, to try to better improve the anemia responses, is a logical next step for the development of luspatercept to treat myelofibrosis-associated anemia.

Source:

Gerds A, Harrison C, Kiladjian J, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis. Blood Advances. Published online May 31, 2024. doi:10.1182/bloodadvances.2024012939