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Luspatercept Demonstrates Promise as Treatment of Anemia in Myelofibrosis

Danielle Ternyila
Published Online:9:00 PM, Wed February 12, 2020
Aaron T. Gerds, MD, MS
Aaron T. Gerds, MD, MS
Myelofibrosis (MF), a myeloproliferative neoplasm (MPN), is associated with high rates of anemia. JAK inhibitors including ruxolitinib (Jakafi) and fedratinib (Inrebic) are the only FDA-approved treatments for this patient population, but JAK inhibition is associated with anemia as well.

“Roughly 40% of patients with MF, or up to 50% in some studies, will have anemia at the time of presentation,” Aaron T. Gerds, MD, MS, said. “Initially, the most common treatment, JAK inhibitors, can lead to even more anemia, and roughly 25% of patients who go on a JAK inhibitor will become anemic overtime.” 

At the 2019 American Society of Hematology (ASH) Annual Meeting, Gerds, assistant professor of Medicine at the Cleveland Clinic Taussig Cancer Institute, presented the findings from a phase II clinical trial that evaluated the safety and efficacy of luspatercept as a treatment of anemia in patients with MF. Although the trial had very stringent criteria for the primary end point, the trial did demonstrate the ability of luspatercept to treat anemia in this particular patient population. 

The FDA previously granted approval to luspatercept-aamt for the treatment of anemia in adult patients with beta-thalassemia who require regular red blood cell transfusions in November of 2019. The approval was based on findings from the randomized, placebo-controlled, double-blind, multicenter phase III BELIEVE trial, in which the primary end point of the study was met.

In the BELIEVE trial, the primary end point was a ≥33% reduction in transfusion burden, with a ≥2 reduction in red blood cell units during weeks 13 to 24 compared with the 12-week baseline period. Overall, 21.4% of patients who received luspatercept achieved the primary end point versus only 4.5% with placebo (95% CI, 10.4-23.6; P <.0001).

In an interview with Targeted Oncology, Gerds discussed the data presented at the 2019 ASH Annual Meeting for luspatercept as a treatment of anemia in patients with MF. He highlighted how these phase II data will impact the upcoming phase III clinical trial, which will further evaluate the safety and efficacy of this treatment option.

TARGETED ONCOLOGY: What was the rationale for evaluating luspatercept as treatment of anemia in this patient population?

GerdsAnemia in MF is a real big problem. Roughly 40% of patients with MF, or up to 50% in some studies, will have anemia at the time of presentation. Initially, the most common treatment, JAK inhibitors, can lead to even more anemia, and roughly 25% of patients who go on a JAK inhibitor will become anemic over time. Anemia causes all kinds of problems, such as AL antibodies, transfusion reactions, and iron overload. Also, the burden of just coming into the cancer center, getting your screening done, waiting for the unit blood, and going through the transfusion [is a problem], so it has a real impact on the quality of life as well. This is why we aimed to target anemia in patients with MF.

TARGETED ONCOLOGY: What was the design of the trial?

GerdsThis was a phase II open-label study of luspatercept in patients with MF who had anemia. There were 4 groups of patients, including patients who were on and off ruxolitinib, and within those 2 groups, there were patients who didn’t get any transfusions and those who are transfusion-dependent. It’s almost a 2 by 2 table if you think about it.

TARGETED ONCOLOGY: What were the findings?

GerdsWe ultimately saw responses in every cohort in this study. The primary outcome was very stringent. For patients not receiving transfusions, it was an increase of a gram and a half in their hemoglobin count over baseline for 12-weeks. Even if their hemoglobin as at a 1.4 increase at some point, they were considered a non-responder. In patients who were receiving transfusions, it was 12-weeks without transfusions, and that was the primary end point up through 169 days.

We saw responses in all cohorts, but perhaps there was a higher response rate in the patients on ruxolitinib with the luspatercept. When you use a less stringent end point, which was 1 of our secondary end points, such as an average hemoglobin increase of a gram and a half over 12 weeks or a 50% reduction in transfusion burden, the response rates were much higher for this more clinically applicable end point.

TARGETED ONCOLOGY: What are the implications of these data?

GerdsThis study served as a basis for planning the phase III study. First, how could we measure the response in these patients better? Second, what is the optimal patient population we should be looking at? Finally, [we aimed] to both inform and help design the upcoming phase III study in MF.

TARGETED ONCOLOGY: Were there any complications with this trial to highlight?

GerdsOne of the other major issues of this trial is looking at safety. We not only want to make sure our drugs are efficacious, but we want to make sure they are safe as well. There were 3 adverse events (AEs) that were most common. One was elevations in blood pressure, another was diarrhea, and the third AE was bone pain, which we had seen in previous studies with this drug in beta-thalassemia anemia and myelodysplastic syndrome. There were no disease-related AEs that led to death. Additionally, all cases of hypertension were able to be controlled medically.

TARGETED ONCOLOGY: What is the current state of affairs for MPNs in general?

GerdsI had the fortunate opportunity this year to present an education session at the annual meeting, and I particularly focused on moving beyond JAK/STAT inhibition. That is the amazing thing about the ASH Annual Meeting; there is so much science, so many new things coming out, and the state of affairs was my job at that education session, to set the table for people going out and viewing the abstracts at this meeting.

I focused on JAK/STAT inhibition and where we are now. We have 2 drugs that are now approved for the treatment of MF. One is for the treatment of polycythemia vera (PV) and 2 JAK inhibitors, which is fantastic. It was a watershed moment for these drugs to come along, and they have become the backbone of our treatment. However, we want to move things forward, and I think these drugs are great because they have improved patient lives dramatically. People are living longer and better, but they also provide a backbone for testing new drugs. For example, JAK inhibition plus drug X or targeting pathway Y. I think that is going to be the next chapter in the story of JAK inhibitors and showing their immense benefit for patients with MPNs.

TARGETED ONCOLOGY: What is your current relationship with the primary care physician?

GerdsInteraction with primary care physicians is so incredibly important for doctors like myself who take care of patients with MPNs for a couple of different reasons. First, it can lend a helping hand and expertise in those challenging cases, but there are so many patients with essential thrombocytopenia and PV out there, and a primary physician might need help going through those things, the diagnosis, or getting treatment started. We could be there to help with those things. Building a strong relationship with your primary care physicians is so very important.

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