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Clinical Data With Pacritinib in Patients With Myelofibrosis
Author(s):
Centering discussion on the JAK inhibitor pacritinib, expert panelists review data from recent clinical trials and consider how they inform real-world use of this agent.
Transcript:
Danielle E. Marcotulli, APN: Dr McCloskey, could you review some of the supporting data for the use of pacritinib in patients with myelofibrosis?
James K. McCloskey II, MD: Looking back at [our scenario patient] JM, you’ll recall that, like most of our patients who started on pacritinib, a couple years into his disease [he returned] to us really cytopenic. And so he had low platelets, he was markedly anemic and with uncontrolled symptoms and splenic enlargement … He had [a platelet count of] less than 50,000. Geeny mentioned the other drugs that we’ve had in this disease space, but none of those really have been extensively studied in patients with significant thrombocytopenia. That’s really why I think we’re so excited about pacritinib. This is a drug that we’ve had … in clinical trials for years, and now I’m really excited to have commercial access to it. It is a novel and new JAK inhibitor, so it is unique from the other ones in my opinion; it’s not the next generation, the next addition, it really is a new drug that targets pathways we have missed previously. Specifically, pacritinib does spare JAK1. In doing so we know that we have a less of an impact on thrombocytopenia because when we hit both JAK1 and JAK2 together, as we do with other JAK inhibitors, we both decrease negative karyotype production and the release of mature platelets into the blood.
In addition, we are targeting IRAK. This is the only drug in this space that we know does this at this time. IRAK is part of the NF-κβ pathway; it’s an inflammatory pathway. You’ve probably heard of IRAK inhibitors in other disease states that are being developed there. It’s exciting new option to target a different pathway other than JAK-STAT, while we recognize the JAK-STAT pathway’s importance in myelofibrosis. This drug does offer us the opportunity to target a different pathway in that disease base. It came to us after a few different clinical trials. PERSIST-1 [NCT01773187] was a randomized clinical trial looking at pacritinib versus best available therapy. Patients were [randomly assigned 2:1] to pacritinib versus best available therapy, and there was not a restriction on platelet count in that trial. What we saw is that there were significant improvements in spleen volume. So if we look at spleen volume response by 35% or more, week 24, this was achieved in 19% of patients on pacritinib compared with 4.7% of patients on best available therapy. Total symptom responses were also … improved: 40% compared with 10% in best available therapy. I think what came out of that trial particularly was that we saw that these patients with significant cytopenias also seem to respond robustly. Specifically, patients with more severe thrombocytopenia are responding with spleen volume reduction by 35% or more with 16% compared with 0% best available therapy.
As an investigator on these early clinical trials, many of us were on phone calls with each other saying, “Hey, I have this patient, and I started him on pacritinib, and he’s no longer receiving transfusions.” And as everyone knows, this is not something we saw previously. We are typically prepared that as we start one of the other JAK inhibitors, such as fedratinib or ruxolitinib, we will predictably have a decrease in the red count and platelet count. And to be frank, this is not something that has scared me. I think I am willing to [deal with] anemia if it’s going to give me a benefit in the long run, but it can be a barrier especially later in disease biology. When we saw patients becoming transfusion independent, which occurred in about [one-fourth] of the patients treated on PERSIST-1, we were all really excited.
This response rate in cytopenic patients led to PERSIST-2 [NCT02055781]. This is the clinical trial that led to the drugs approval. This is a randomized clinical trial looking at best available therapy versus pacritinib, also known as Vonjo. Patients were eligible if they had platelet counts of less than 100,000. When we look at the patients who came on to this, they were significantly cytopenic, about [one-fourth] of the patients were transfusion dependent, medium platelet count was about 55,000, so these were pretty sick patients. And again, when we see these data, I think what was important [was] … it was best available therapy. The most common treatment on the best available therapy arm was ruxolitinib. It wasn’t a placebo-controlled trial, and so when we see the response rates, for me it always reflects … the real world before pacritinib. I think it explains why the disease has been so frustrating to manage, because when we looked at response rates, there was a spleen volume response by 35% or more in 30% of patients on the pacritinib arm compared with only 3% of patients in the best available therapy arm’ again I think, a lot of these people are on ruxolitinib. Twenty-six percent of patients achieved a 50% reduction in their total symptom score compared with 9% of patients on best available therapy. And we saw a transfusion requirement decreased in at least [one-fourth] of patients with a mean hemoglobin rise by 2 g/dL or more in 25% of patients compared with 12% on best available therapy.
We’ve been using ruxolitinib for a long time now, we’ve been using it in patients with lots of cytopenias, and I did, too, because we did not have other options. But I think that looking at the PERSIST-2 data, [they] really emphasize the importance of considering other options now that we have them and not forgetting that these other options are there for us. We’ve been so used...to patients staying on a suboptimal dose of ruxolitinib, and it can be difficult to entice them to change treatments. And lastly, we do have still the PACIFICA trial [NCT03165734] accruing and we have this trial at Hackensack. This was a large multinational study looking at pacritinib in patients with primary secondary myelofibrosis with intermediate high-risk disease and platelet count less than 50,000. It’s going to continue to give us more data on the drug and the outcomes for these patients. It is mostly accruing in Europe now because it is approved here in the United States, but I think [those are] the data that [we] will continue to look forward to.
Transcript is AI-generated and edited for clarity and readability.
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