Pacritinib in Myelofibrosis


Raajit Rampal, MD, PhD, reviews data from the PERSIST trials which support the use of pacritinib for myelofibrosis treatment.

Case: A 67-Year-Old Man With Myelofibrosis

Initial presentation

RF is a 67 y/o man who visits his primary care physician for his yearly checkup. He reports having fatigue and bone pain for the last few months. More recently, he’s been complaining of abdominal discomfort which he thinks is probably related to the big Thanksgiving dinner party, he and his wife hosted.

He enjoys spending time working on antique cars in his garage, but his wife says he becomes tired after just an hour.

RF has not noticed any changes in his eating habits, but his wife mentions he doesn’t eat as much as he used too. Upon examination, RF has lost close to 13 lbs. since this last yearly exam.


Primary myelofibrosis diagnosed about 1 year ago

Diabetes (controlled with diet and exercise)


SMH: Smoked 3 packs/day but quit 5 years ago; he drinks occasionally

PE: abdominal exam reveals spleen palpable 5cm below left coastal margin, visible bruising

Initial Labs/Workup:

Platelet count: 184 x 109/L

Hgb: 10g/dL

WBC: 34 x 109/L

Bone Marrow Biopsy

Shows an increase in megakaryocytes

Bone Marrow Fibrosis

Megakaryocyte Atypia

Molecular testing

JAK-V617F mutation: positive

Initial treatment:

Patient was started on ruxolitinib 10mg BID when initially diagnosed

Current Presentation/Labs:

One year later, RF reports increasing fatigue and abdominal pain

Current Labs:

Platelet count: 57 x 109/L

Hgb: 8g/dL

WBC count: 29 x 109/L

Raajit Rampal, MD, PhD: Let's talk about 2 studies that support the use of pacritinib. One is the PERSIST-1 study. PERSIST-1 was a randomized trial in which patients were randomized to pacritinib of 400 mg daily versus best available therapy that was exclusive of a JAK inhibitor. This study did not restrict patient enrollment based on their platelet counts. That's an important distinction to remember versus the COMFORT trials that looked at patients with 100,000 platelets or higher, or the JAKARTA study. The JAKARTA2 study looked at patients with 50,000 platelets and higher while PERSIST had patients with an unrestricted platelet count upon entry. The end points for PERSIST-1 were spleen volume reduction by 35% and total symptom score reduction by 50% or more. In the PERSIST-1 study, overall data supported that pacritinib did have a statistically significantly improved response rate versus what we've seen with best available therapy in patients with an unrestricted platelet count. Notable adverse effects of the drug that were seen in both studies included gastrointestinal [GI] adverse effects as well as dizziness and peripheral edema. In the PERSIST-2 study, the patients in this study were patients who could have been exposed to a JAK inhibitor—either 1 or 2 JAK inhibitors—previously. Patients in this study were randomized to pacritinib 400 mg daily, 200 mg twice daily, or best available therapy that could include a JAK inhibitor. In this particular study, the end points were the same, which again were spleen volume reduction, as well as total symptom score reduction. Overall, the study showed that as a composite, the pacritinib arms trended towards superiority versus best available therapy. But in the pacritinib 200 milligrams twice-daily arm, there was a significant reduction in both spleen volume as well total symptom score. Again, these are patients who could have been previously treated with a JAK inhibitor. One important thing to remember with PERSIST-2 is that it was restricted to patients with a platelet count of less than 100,000. Looking at the cytopenic patient population that we just described a moment ago, and again, to drive home the point, this is a patient population that was really not the focus of the study in the COMFORT-l or COMFORT-II studies. It's a somewhat distinct patient population. Again, in both of these studies, pacritinib did demonstrate superiority versus the comparator arms in treating these patients with essentially cytopenic MF [myelofibrosis]. In terms of the adverse effects that we talked about a moment ago, it's important to remember that pacritinib not only inhibits JAK2 but also has an FLT3 inhibitor activity as well. And most likely accounts for some degree of GI adverse effects that we've seen which were most commonly diarrhea. However, this can be managed with over-the-counter medications such as loperamide [Imodium]. It is often important to think about prophylaxing a patient with drugs like loperamide so that GI adverse effects don't have a chance to get out of control as the patient is starting therapy. If we take this back, all of this data into the context of what we are dealing with our patient RF. We've gone from a state where the patient was doing somewhat well on ruxolitinib to where the patient's counts have really declined, which in practicality would limit the dosing of ruxolitinib. The patient was started on 10 mg twice daily but per the label, if the platelet count is between 50,000 and 100,000, the dose really should be reduced to 5 mg twice daily. This presents a challenge in and of itself because if one looks at composite data from the COMFORT studies, the dosing effects of ruxolitinib are apparent—meaning that when dosing is 10 mg twice daily or higher, that is really where the maximal spleen volume response as well as symptom response is seen. A dose of 5 mg twice daily does not seem to have the same effect as a dose of 10 mg twice daily. Not only do we have a patient whose symptoms are progressing but we are in a situation where we have to dose reduce the ruxolitinib which will likely further efficacy. These are some of the challenges that we face in a case such as this. Again, if we were to take this case and look at this case 5 years ago when we did not have alternative therapies, the likely prognosis for this patient is quite poor with a median life span of perhaps 14 months.

Transcript edited for clarity.

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