John Mascarenhas, MD
Patients with myelofibrosis and thrombocytopenia had significantly greater reductions in spleen volume and symptoms when treated with the multikinase inhibitor pacritinib, compared with the best available therapy (BAT), a randomized trial showed.
The results showed that 18.1% of patients treated with pacritinib had at least a 35% reduction in spleen volume, as compared with 2.8% of patients randomized to BAT, which could include the first-generation JAK2 inhibitor ruxolitinib. A fourth of pacritinib-treated patients had at least a 50% reduction in total symptom score, versus 13.9% in the BAT group.
Patients were randomized to 2 different pacritinib dosing schedules (200 mg twice a day and 400 mg every day), and both appeared more effective than BAT. However, only the higher dose resulted in significantly greater improvement in both outcomes compared with BAT, as reported at the American Society of Hematology meeting in San Diego.
“Spleen volume reduction and total symptom score responses to pacritinib twice a day were consistent across demographic and disease risk characteristics,” said John Mascarenhas, MD, assistant professor of medicine of hematology/oncology at Mount Sinai Medical Center in New York. “Pacritinib twice a day appeared to have a better benefit/risk profile than the best available therapy, which included ruxolitinib.”
How the results affect pacritinib’s regulatory status remains to be seen. The FDA placed the agent on full clinical hold in February, amid concerns about interim survival results from the trial, bleeding, and cardiovascular events. The FDA subsequently allowed patients who were benefiting from pacritinib to resume using the drug under a single-patient IND/compassionate use program.
Mascarenhas reported final results from the PERSIST-2 trial. The earlier PERSIST-1 trial demonstrated sustained spleen volume reduction (SVR) and symptom control with pacritinib versus BAT (excluding ruxolitinib) in patients with myelofibrosis, irrespective of baseline platelet count.1
PERSIST-2 continued the evaluation of pacritinib (which targets FLT3, IRAK1, and CSF 1R, in addition to JAK2) in patients with platelet counts ≤100,000 and expanded the definition of BAT to include ruxolitinib. The trial design also included every day and twice a day dosing of pacritinib, as pharmacokinetic studies predicted that 200 mg twice a day would result in a narrower peak-trough range as compared with 400 mg every day. Patients could cross over from BAT to pacritinib at any time during the trial or at week 24.
PERSIST-2 had coprimary endpoints: the proportion of patients attaining ≥35% SVR and the proportion achieving ≥50 reduction in total symptom score, both assessed after 24 weeks of follow-up. Investigators randomized 311 patients to the 2 groups with different doses of pacritinib or BAT.
Analysis of baseline characteristics showed that 60% to 70% of the patients had diagnoses of primary myelofibrosis, and half of the patients met Dynamic International Prognostic Scoring System (DIPSS) criteria for intermediate-2 risk category. The patients had a median spleen length of 13 to 15 cm, and 40% to 50% of patients had platelet counts <50,000/mcL. About 40% of the patients had previously received ruxolitinib.
The efficacy analysis included 222 patients. The data showed that 21.6% of patients in the pacritinib twice a day arm attained ≥35% SVR (P = .001 versus BAT), as did 14.7% of patients in the pacritinib every day arm (P
= .017), resulting in an overall rate of 18.1% for the 2 arms combined (P
Analysis of total symptom score showed that 32.4% of patients had ≥50% reduction with pacritinib twice a day (P
= .011 versus BAT), 17.3% with pacritinib every day (P
= .652), and 24.8% for the 2 pacritinib arms combined (P
Subgroup analysis showed a consistent effect of pacritinib across most prespecified patient groups. Quality-of-life data showed that patients assigned to BAT were substantially more likely to report no change or worsening of their condition, and patients in the pacritinib groups were more likely to report noticeable improvement.
Overall survival data (censored as of the FDA clinical hold) showed 15 deaths in the pacritinib every day arm, 10 deaths in the twice a day arm, and 14 deaths in the BAT arm. After the clinical hold, 7 additional deaths occurred in the pacritinib every day arm, 9 in the pacritinib twice a day arm, and 6 in the BAT group. Mascarenhas said 7 deaths occurred after crossover from BAT to pacritinib.
Analyses of secondary endpoints showed that patients treated with pacritinib required fewer red blood cell transfusions, and patients in the pacritinib twice a day group had substantially greater improvement in baseline platelet count among those patients who had platelets counts ≤50,000 at enrollment.