SAN DIEGO – Late-breaking results from the phase III PERSIST-2 trial may ease at least some safety concerns surrounding the use of pacritinib in patients with myelofibrosis, investigators said at the annual meeting of the American Society of Hematology.
In February 2016, the Food and Drug Administration imposed a clinical hold on studies of pacritinib in the wake of concerns about excess deaths, cardiotoxicities, and hemorrhage. But in the final data analysis presented at ASH, rates of these outcomes were low and similar among patients randomized to pacritinib once daily, pacritinib twice daily, or best available treatment for myelofibrosis, including ruxolitinib, lead investigator John Mascarenhas, MD, said.
Indeed, more patients died of progressive disease after stopping pacritinib than died of treatment-associated adverse events, said Dr. Mascarenhas of Icahn School of Medicine at Mount Sinai, New York.
Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. In the previous phase III PERSIST-1 trial, patients who received pacritinib had a fourfold greater probability of experiencing at least a 35% decrease in splenic volume than did patients who received best available treatment (P = .003).
PERSIST-2 also yielded clear efficacy signals, particularly when patients took pacritinib twice daily, said Dr. Mascarenhas. Between baseline and week 24, splenic volume dropped by at least 35% in 22% of these patients (95% confidence interval, 13%-33%), compared with 3% of patients on best available treatment (95% CI, 0.3%-10%; P = .001). Patients who took pacritinib twice daily also had a 32% (95% CI, 22%-44%) chance of experiencing at least a 50% drop in symptoms such as fatigue, bone pain, itching, and abdominal pain, compared with 14% (95% CI, 7%-24%) of patients on best available treatment (P = .01).
Demographic and disease risk characteristics did not significantly affect the chances of reaching these coprimary endpoints, Dr. Mascarenhas noted. “My humble opinion as a clinical investigator is that [pacritinib] is an effective drug, with a favorable benefit-to-risk ratio,” he said.
Several hematologists who were not involved in this trial agreed. “I don’t see why you are nervous [about presenting these results],” noted hematologist Kanti Rai, MD, of the Feinstein Institute for Medical Research in Manhasset, N.Y., told Dr. Mascarenhas during the discussion after the data were presented, prompting laughter from the audience.
It remains to be seen whether the FDA will find the data convincing enough to lift the clinical hold on pacritinib. Ruxolitinib (Jakafi) is approved to treat splenomegaly and symptom burden in myelofibrosis but is associated with dose-limiting cytopenias and cannot be used in patients with platelet counts of less than 50,000/mcL.
PERSIST-2 compared pacritinib 400 mg once daily with pacritinib 200 mg twice daily and best available treatment, including ruxolitinib, in patients with primary or secondary myelofibrosis and less than 100,000 platelets/mcL. About half of the study patients had less than 50,000 platelets/mcL, and more than 40% had previously received ruxolitinib.
When the clinical hold on pacritinib went into effect, 221 patients had reached the 24-week designated study endpoint and were included in the intention-to-treat analysis, Dr. Mascarenhas reported. Censored Kaplan-Meier curves of overall survival favored pacritinib over best available treatment, although the difference in survival rates did not reach statistical significance (hazard ratio, 0.68; 95% CI, 0.3-1.5). A total of 9% of patients in the twice-daily pacritinib group died, compared with 14% of patients receiving pacritinib once daily or best available treatment.
Twice-daily pacritinib most often led to diarrhea (48% of patients), nausea (32%), thrombocytopenia (34%), and anemia (24%). Overall rates of serious treatment-emergent adverse events were seen in 47% of the two pacritinib groups and in 31% of patients receiving best available treatment. The most common serious treatment-emergent adverse event with twice daily pacritinib was anemia (8% of patients), followed by thrombocytopenia and pneumonia (6%). Heart failure, atrial fibrillation, and cardiac arrest were rare and similar across all three treatment groups, as were epistaxis and subdural hematoma.
This is the first randomized, controlled trial of patients with myelofibrosis and thrombocytopenia, according to Dr. Mascarenhas. “This was a patient population with low platelets and at risk of poor outcomes, and they did pretty well,” he said. “There really is no therapeutic option for patients with myelofibrosis and low platelets, and [pacritinib] offers patients in this vulnerable situation an opportunity for symptom relief. I hope to see it move forward.”
CTI Biopharma sponsored the study. Dr. Mascarenhas disclosed research funding from CTI Biopharma.