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.
Published on: December 06, 2016
(San Diego, December 6,
2016) – 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.
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; Richele.Keas@fleishman.com
Stephen Fitzmaurice, ASH
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(561) 506-6890; email@example.com