March 19, 2018
3 min read

Pacritinib reduces splenomegaly, symptoms in myelofibrosis

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Aaron T. Gerds

The JAK2 inhibitor pacritinib appeared more effective than best available therapies for reducing splenomegaly and symptoms among patients with myelofibrosis and thrombocytopenia, according to study results published in JAMA Oncology.

Ruxolitinib (Jakafi, Incyte), a JAK1/JAK2 inhibitor, is the only FDA-approved treatment for myelofibrosis.

“Ruxolitinib has been a touchstone for treating the disease, but it has its drawbacks,” Aaron T. Gerds, MD, assistant professor of medicine at Cleveland Clinic and a HemOnc Today Next Gen Innovator, told HemOnc Today. “It doesn’t work for everyone forever. A patient’s disease will eventually progress at some point, whether it’s in symptoms, spleen size or to a more accelerated phase. Also, there are limitations with cytopenias.”

The multicenter, randomized phase 3 PERSIST-2 study included 311 patients (mean age, 63.7 years; 55% men) with myelofibrosis and platelet counts of 100 x 109/L or lower.

Gerds and colleagues randomly assigned patients to three regimens: 400 mg pacritinib (CTI BioPharma) once daily (n = 75), 200 mg pacritinib twice daily (n = 74), or best available therapy (n = 72).

Study protocol allowed crossover from best available therapy after 24 weeks, or for the progression of splenomegaly.

A 35% or greater spleen volume reduction and a 50% or greater total symptom score reduction at 24 weeks served as independent coprimary endpoints.

Nearly half of patients (48%) had received prior ruxolitinib.

Ruxolitinib was the most commonly used best available therapy (45%; n = 44). Nineteen patients (19%) underwent watchful waiting.

The pacritinib regimens appeared more effective for the production of a 35% or greater reduction in spleen volume than best available therapy (18% vs. 3%; P = .001).

Twice-daily pacritinib appeared significantly more effective than best available therapies for 35% or greater spleen volume reduction (22% vs. 3%; P = .001), and for reduction of 50% or more of total symptom score (32% vs. 14%; P = .01).

Patients assigned twice-daily pacritinib demonstrated the greatest clinical improvement in hemoglobin and reduction in transfusion burdens.

The most common grade 3 or grade 4 adverse events in all treatment groups included thrombocytopenia (31% for once-daily pacritinib; 32% for twice-daily pacritinib; 18% for best available therapy) and anemia (27% for once-daily pacritinib; 22% for twice-daily pacritinib; 14% for best available therapy).

Fifteen patients (14%) discontinued treatment due to adverse events in the once-daily pacritinib group, compared with 10 patients (9%) in the twice-daily pacritinib group and four patients (4%) in the best available therapy group.

Researchers acknowledged the study was limited by a clinical hold imposed by the FDA in response to intracranial hemorrhage and patient deaths from cardiac failure in the related PERSIST-1 trial. The hold reduced the sample size of patients who reached 24 weeks of treatment. The hold also compromised time-to-event endpoints — such as OS — and reduced follow-up time.

“The bottom line is, pacritinib was better at shrinking people’s spleens than ruxolitinib, and there was a trend toward improvement in total symptom burden with pacritinib at 24 weeks,” Gerds said. “In the end, it does appear to be a very safe drug.”

The future of JAK inhibitors for myelofibrosis remains uncertain, Maximilian Stahl, MD, and Amer Zeidan, MBBS, MHS, both of the department of internal medicine at Yale University, wrote in an accompanying editorial.

“In moving pacritinib forward in clinical development, lessons can be learned from the other JAK2 selective inhibitor fedratinib [Sanofi],” they wrote. “The clinical development of fedratinib [also was] far progressed when the manufacturer discontinued all trials of the drug after the FDA imposed a clinical hold when several patients developed Wernicke encephalopathy in 2013.”

The hold later lifted, and fedratinib is expected to be submitted for FDA approval, Stahl and Zeidan wrote.

“In the spirit of the German poet Goethe, there is still a long road ahead and significant effort will be required to get both more effective and safer JAK2 inhibitors approved,” they wrote. “It remains to be seen whether other novel non-JAK2-mediated therapies will be the future of progress in myelofibrosis therapy.” – by Andy Polhamus


For more information:

Aaron T. Gerds, MD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email:


Disclosures: Gerds reports consultant or advisory roles with AstraZeneca, CTI BioPharma and Incyte. Please see the full study for all other authors’ relevant financial disclosures. Zeidan reports consultant roles with or honoraria from Ariad, Celgene, Gilead, Incyte and Pfizer.