PERSIST-1 and PERSIST-2 Trials in Myelofibrosis

Srdan Verstovsek, MD, PhD: If the JAK/STAT [Janus kinase and signal transducer and activator of transcription] pathway is a uniform, always-present, intracellular signaling pathway that is hyperactive in all the patients’ myelofibrosis, we need to account for its presence—and we do. We have JAK inhibitors, including pacritinib, that would inhibit that particular pathway to extent possible. With that, it decreases the amount of proliferation and improves the patients’ quality of life. But we know, particularly in patients with a low JAK2 allele burden, for example, where the number of cells in the sample of the patients gives us a clue that this pathway is not the only parameter leading to the disease existence. For example, you have patients with advanced myelofibrosis with the JAK2 mutation that has only, let’s say a 15% JAK2 allele burden. That means 15% of the cells in the sample are affected by the mutations and activate the JAK/STAT pathway. What about the other components of the biology of that disease in those particular patients? Here is a possible role of IRAK2 [interleukin-1 receptor-associated kinase 2] receptor on an IRAK1 [interleukin-1 receptor-associated kinase 1] pathway that activates the NF kappa B, a central protein involved in the enhancement production of the cytokines. Cytokines are part of inflammatory disease. Therefore, having a medication like pacritinib, for example, that will do dual things, inhibition of JAK2 and IRAK1 may potentially provide extra benefit to the patients. Particularly patients with a low blood cell count, in which you can deliver pacritinib because it’s not myelosuppressive, and you cannot deliver ruxolitinib and fedratinib in optimal doses.

Aaron Gerds, MD, MS: The 2 randomized phase 3 trials of PERSIST-1 and PERSIST-2 trials were focusing on looking at pacritinib in patients with myelofibrosis. Although these were randomized, controlled trials of a JAK inhibitor vs placebo, or best available therapy, the 1 thing that sets apart the PERSIST studies is that patients who are thrombocytopenic were included. If we look at the COMFORT [Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment] studies and the JAKARTA studies—the studies that ultimately lead to the approval of ruxolitinib and fedratinib—as well as ongoing studies with other JAK inhibitors, we see there seems to be a hard platelet cutoff at 50,000. Any patient with this kind of myelodepletion or thrombocytopenic myelofibrosis were not included, and that is a sizable population of patients that now don’t have an approved therapy. Thus, the PERSIST trials, the subsequent PAC203 trial, and the ongoing PACIFICA trial are trying to address an area of need.

Looking at PERSIST-1 and PERSIST-2, the key take-home point was that, in patients who had thrombocytopenia, there were improvements in symptom burden and spleen response. If we look across the development of pacritinib, whether we’re talking PERSIST-1, PERSIST-2—although the PAC203 was a single-arm study, we could draw parallels from what we’d expect in that population—we see that a larger proportion of patients had spleen volume reduction and symptom burden improvement than what we would expect with other therapies that are available. There have been a phase 2 study and a pilot study looking at low-dose ruxolitinib patients with low platelet counts, with modest proportions of patients having a decent spleen volume reduction or symptom burden. The amount of patients that have those positive end points are larger when they are treated with pacritinib as compared with ruxolitinib, placebo, or observation, of course. The second major take-home point is that this was done safely. There was an initial concern that there were excess bleeding-related events and cardiac events in patients treated with pacritinib, and that ultimately lead to the FDA [Food and Drug Administration] hold on development of pacritinib. But with additional information, the remainder of the data that was sent in, as well as the results from the PAC203 study, showed 2 things: That this patient population was really sick, and even when you give them pacritinib, they can do well without excess toxicity compared with patients who are just generally sick with myelofibrosis. Those are the key pieces from the PERSIST-1, PERSIST-2, and the PAC203 studies.

Srdan Verstovsek, MD, PhD: Pacritinib is the JAK2 and IRAK1 inhibitor that has been around for quite some time. I would like to highlight the PERSIST-1 and PERSIST-2 studies. These were randomized studies either in the frontline setting or in patients with low platelets, respectively. In these studies, what we learned that is of particular interest today is its ability to improve the quality of life and improve the spleen size—the 2 out of 3 parameters I mentioned as the major problems in patients with myelofibrosis—in patients with low platelets. Remember the ruxolitinib and fedratinib are approved therapies, but not to be given in patients with platelets below 50, for example, because they may worsen that platelet number and cause anemia. These are adverse effects that are not compatible with optimal care. Even in patients with platelets between 50 and 100, ruxolitinib, for example, is usually delivered in suboptimal doses, and it’s not providing optimal clinical care for those patients. Thus, knowing in subgroup analysis that in these patients with low platelets, particularly in platelets before 50, pacritinib is valuable because, for a significant number of patients, it would control the spleen and the symptoms. Furthermore, there is a signal here that it may also make people transfusion independent. In about the 25% of the patients that are transfusion dependent—now I’m talking about the anemia benefit—it may make them transfusion independent. Thus, particularly in those patients, to summarize, you have a drug that works through 2 mechanisms in parallel that would lead to improvement in the spleen, improvement in quality of life, and also potentially improve the anemia parameters in selected patients.

Transcript Edited for Clarity