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New Data Shed Light on Potential Advantages of Pacritinib for Patients with Myelofibrosis

Pacritinib, currently on hold by the FDA, appears to be more effective in reducing spleen volume; twice-daily dose improves symptoms. This analysis comes from data before the clinical hold.

Compared with standard therapy, pacritinib significantly reduces spleen size among people with myelofibrosis who have very low levels of platelets, according to a late-breaking study being presented today during the 58th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego. The study investigators also reported that patients taking a twice-daily dose of this investigational oral multikinase inhibitor experienced significant improvements in symptoms.

Myelofibrosis is a chronic, potentially life-threatening blood cancer that affects approximately 20,000 Americans. The condition is associated with inflammation and scarring in the bone marrow, which disrupts the production of blood cells and can cause severe anemia, weakness, and fatigue. As the liver and spleen begin to take over blood cell production, these organs can become enlarged. People with an enlarged spleen are more prone to infection, anemia, potentially fatal bleeding or rupture, and abdominal discomfort and weight loss, so finding effective treatments to reduce spleen size is important for this group of patients.

PERSIST-2, an open label, Phase III study, was designed to compare the safety and efficacy of pacritinib with currently available therapies, including ruxolitinib, a JAK2 inhibitor approved by the U.S. Food and Drug Administration (FDA) in 2011 to treat intermediate- or high-risk myelofibrosis. The challenge, researchers explain, is that ruxolitinib is not indicated for people with platelet counts under 50,000 per microliter (μl), who represent approximately one-third of myelofibrosis patients. These patients are at much greater risk for complications and have limited to no treatment options.

“Despite the fact that these patients have very low platelet counts and in approximately 45 percent of the cases had previously been treated with ruxolitinib, we were able to administer this drug effectively, thereby significantly reducing spleen volume and also significantly improving symptoms in a subset of patients who received pacritinib twice daily,” said lead study author John Mascarenhas, MD of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York. “This is a very vulnerable patient population. My hope is that pacritinib might become an option for them because even though ruxolitinib is well tolerated, one of the downsides is often myelosuppression, and many patients with myelofibrosis start with low baseline platelet counts.” 

Researchers say this study builds on the results seen in the earlier PERSIST-1 trial, and specifically provides more insight into the optimal dosing of pacritinib, as well as its safety in patients with very low platelets. The FDA imposed a clinical hold on studies of pacritinib earlier this year due to safety concerns about increases in risk of bleeding and cardiac events. But according to Dr. Mascarenhas, the full data analyses do not show a significant difference in deaths across groups; during the course of the study, 10, 15, and 14 patients died in the pacritinib twice daily, once daily and best available treatment groups, respectively. Similarly, cardiac and bleeding events were rare and comparable. “The safety profile remains reasonable given the fact that we are treating patients with low platelet counts who are already at risk for both bleeding and cardiac events,” he said. 

A total of 221 out of the originally intended 311 patients with platelet counts ≤100,000/ μl were randomly assigned to receive pacritinib at either 200 mg twice daily or 400 mg once daily or best available therapy. About half of the PERSIST-2 study population had platelet counts <50,000 μl. The proportion of patients who had ever taken ruxolitinib was 41 percent of the pacritinib group and 46 percent in the best available therapy arm. The two co-primary endpoints were the percentage of patients achieving 35 percent or greater reduction in spleen volume as measured by MRI or CT scan and a 50 percent or more improvement in symptoms such as fatigue, bone pain, itching, and abdominal pain. At the time that the clinical hold went into effect, 221 patients had reached the 24-week mark (the designated study endpoint) and were included in the intent-to-treat analysis to evaluate efficacy.

Data show that 18 percent of patients who received pacritinib achieved a 35 percent or greater reduction in spleen size from baseline to week 24 compared to just 3 percent of those in the best available treatment arm. Even though a higher proportion of patients receiving pacritinib reported improvements in their symptoms compared with those given best available therapy (25% vs 14%, respectively), the difference was not statistically significant. However, when researchers looked only at patients who received twice daily pacritinib, one-third (32%) reported a 50 percent or more reduction in symptoms compared with just 14 percent of best available therapy patients, which did reach statistical significance. 

Ruxolitinib is a JAK1/2 inhibitor. Pacritinib inhibits JAK2 and FLT3 as well as other enzymes that Dr. Mascarenhas said may influence its clinical efficacy and side effect profile. “The fact that there are other kinases that are inhibited beyond JAK2 may potentially explain why, for example, we saw 25 percent anemia response in PERSIST-1 with this drug that was not seen with ruxolitinib.” 

The most common adverse events related to pacritinib were diarrhea, vomiting, nausea, anemia, and low platelets. Serious cardiac events and bleeding events were relatively rare and comparable between all groups. 

The study was funded by CTI BioPharma. 

John Mascarenhas, MD, Associate Professor of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, N.Y., will present this study, titled “Results of the Persist-2 Phase 3 Study of Pacritinib (PAC) versus Best Available Therapy (BAT), including Ruxolitinib (RUX), in Patients with Myelofibrosis and Platelet Counts <100,000/μL,” (LBA-5) during the late-breaking abstracts session on Tuesday, December 6 at 7:30 a.m. PST in Hall AB.

For the complete annual meeting program and abstracts, visit www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH16 on Twitter and like ASH on Facebook for the most up-to-date information about the 2016 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, as well as the newly launched, online, open-access journal, Blood Advances (www.bloodadvances.org).

Richele Keas, FleishmanHillard
(703) 731-3237; [email protected]

Stephen Fitzmaurice, ASH
(561) 506-6890; [email protected]