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Pacritinib more effective than best available therapy for myelofibrosis with low platelets
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SAN DIEGO — Pacritinib more effectively led to spleen volume reduction than best available therapy in patients with myelofibrosis and platelet counts less than 100,000/µl, including those who had previously received a JAK2 inhibitor, according to results of the PERSIST-2 trial presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.
Further, pacritinib (CTI BioPharma) twice-daily dosing appeared more active than once-daily dosing and significantly led to spleen volume reduction and improvement in total symptom score compared with best available therapy.
“A quarter of patients with myelofibrosis present with thrombocytopenia, and a platelet count less than 50,000/µl is a recognized adverse prognostic factor, associated with reduced quality of life, significant symptom burden and a shorter survival,” John Mascarenhas, MD, associate professor of medicine, hematology and medical oncology at The Tisch Cancer Institute of Mount Sinai Health System, said during his presentation. “The approved JAK1/2 inhibitor, ruxolitinib [Jakafi, Incyte] reduces splenomegaly symptoms but is associated with dose-limiting cytopenias and is not indicated for patients with a platelet count less than 50,000/µl.”
The randomized phase 3 PERSIST-1 trial showed pacritinib induced sustained spleen volume reductions and improved symptom control compared with best available therapy in patients with myelofibrosis, regardless of their platelet count.
However, pacritinib was placed on a full clinical hold by the FDA in February 2016 due to concerns over interim survival results, bleeding and cardiovascular events.
“This study adds more safety data to the PERSIST-1 study and the earlier-phase studies,” researcher Aaron T. Gerds, MD, hematologist at Cleveland Clinic, told HemOnc Today. “By putting this all together and pooling it, we’ll get a better sense of the risk–benefit ratio for patients, and whether this medication should move forward and be made available for the patients who desperately need this treatment.”
Results of PERSIST-2
The PERSIST-2 trial included 311 patients assigned pacritinib twice daily (n = 107; 200 mg), pacritinib once daily (n = 104; 400 mg) or best available therapy (n = 100). All patients had a platelet count less than 100,000/µl.
The co-primary endpoints including the proportion of patients who achieved at least a 35% reduction in spleen volume and at least a 50% reduction in total symptom score from baseline to week 24. The primary objective was to compared the pooled pacritinib data with data from the best available therapy arm; a secondary objective was to compare the pacritinib dosing arms individually with the best available therapy arm.
Of the patients, 221 were included in the intent-to-treat efficacy analysis — which included 74 patients (median age, 67 years; 64.9% men) in the pacritinib twice-daily arm, 75 patients (median age, 69 years; 50.7% men) in the pacritinib once-daily arm, and 72 patients (median age, 69 years; 54.2% men) assigned best available therapy — because they had a randomization date that allowed for an analysis at week 24 prior to the full clinical hold.
The percentage of patients with platelet counts less than 50,000/µl was 51% on the one-daily arm, 42% on the twice-daily arm and 44% on the best available therapy arm. Forty-one percent to 46% of patients had previously received ruxolitinib therapy.
In the best available therapy arm, 45% of patients received ruxolitinib, 19% received hydroxyurea and 19% underwent a watch-and-watch approach.
“This highlights the fact that this is an area where there really is no other viable therapeutic option for these patients,” Mascarenhas said.
At week 24, spleen volume reduction of at least 35% occurred in more patients in both pacritinib arms (18.1%; P = .001), the one-daily arm (14.7%; P = .017) and the twice-daily arm (21.6%; P = .001) compared with the best available therapy arm (2.8%).
Total symptom score reduction of at least 50% occurred in 13.9% of patients on the best available therapy arm, compared with 24.8% of patients in both pacritinib arms, 17.3% of patients on the once-daily arm, and 32.4% of patients on the twice-daily arm (P = .011), the latter of which was the only difference to meet statistical significance.
“Pacritinib-treated patients enjoyed improvement in each symptom that contributed to the total symptom score,” Mascarenhas said.
Researchers observed no significant difference in survival outcomes among patients in the pacritinib once-daily arm (HR = 1.18; 95% CI, 0.57-2.44) and twice-daily arm (HR = 0.68; 95% CI, 0.3-1.53) compared with patients in the best available therapy arm.
Among transfusion-dependent patients at baseline, those treated with pacritinib had lower red blood cell transfusion requirements than those treated with best available therapy at week 12 and week 24. Median number of transfusions decreased from 1.49 to 1 among those treated with pacritinib once daily, from 1.06 to 0.67 among those treated with pacritinib twice daily, and from 1.71 to 1.33 among those treated with best available therapy.
Previous safety concerns
All patients exposed to study treatment were included in safety analyses.
More patients in the once-daily than twice-daily and best available therapy arms experienced dose interruptions (38% vs. 27% vs. 10%), dose reductions (20% vs. 12% vs. 7%) and discontinuation (19% vs. 15% vs. 12%) due to adverse events.
The most common treatment-emergent adverse events included diarrhea (once daily, 67%; twice daily, 48%), nausea (once daily, 38%; twice daily, 32%), anemia (once daily, 28%; twice daily, 24%) and thrombocytopenia (once daily, 33%; twice daily, 34%).
Serious treatment-emergent adverse events occurred in 46% of patients on the once-daily arm, 47% of the twice-daily arm, and 31% of the best available therapy arm. The most common serious advents were anemia, thrombocytopenia, pneumonia and acute renal failure.
Cardiac events and bleeding were relatively infrequent in this study, Mascarenhas said.
After the full clinical hold, there were seven deaths in the once-daily arm, 10 deaths in the twice-daily arm and six deaths in the best available therapy arm.
“It’s important to note that progression of disease was the leading cause of death in the twice-daily dose arm,” Mascarenhas said. “This was after the patients stopped the drug when the drug was on clinical hold.
“Despite study truncation due to the clinical hold, pacritinib was significantly more effective than best available therapy, including ruxolitinib, for spleen volume reduction and trending toward improvement for total symptom score,” he added.
Regardless of the clinical hold and toxicity concerns, the benefit–risk ratio appears to be in favor of pacritinib, Mascarenhas said.
“For patients with low platelets, there really is no viable therapeutic option,” he added. “This offers patients in this vulnerable situation an opportunity to afford symptom relief. I think this is a drug that hopefully will move forward.” – by Alexandra Todak
Reference:
Mascarenhas J, et al. Abstract LBA-5. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016.
Disclosure: The study was funded by CTI BioPharma. Mascarenhas reports consultant roles with and research funding from CTI BioPharma, Janssen, Incyte, Novartis and Promedior. Gerds reports research funding from AstraZeneca, CTI BioPharma, Incyte and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.