© ASCO/Zach Boyden-Holmes
CHICAGO—The JAK2/FLT3 inhibitor pacritinib may fulfill an unmet need in the treatment of myelofibrosis (MF), according to a speaker at the 2015 ASCO Annual Meeting.
Results of the phase 3 PERSIST-1 trial indicate that pacritinib is safe and effective for MF patients with thrombocytopenia.
“Thrombocytopenia is a common feature in people with advanced [MF], and current treatment options have not been able to concurrently improve splenomegaly symptoms and cytopenias in these patients,” said study investigator Ruben A. Mesa, MD, of the Mayo Clinic Cancer Center in Scottsdale, Arizona.
But PERSIST-1 showed that pacritinib can accomplish this. And the drug proved more effective than best available therapy (BAT), excluding JAK inhibitors, in reducing spleen volume and alleviating MF symptoms in the entire cohort of MF patients.
Dr Mesa presented these results at ASCO as abstract LBA7006. The study was funded by CTI BioPharma Corp., the company developing pacritinib.
The trial included 327 patients who were randomized to receive pacritinib (n=220) or BAT (n=107).
Patients in the BAT arm received therapies that are routinely prescribed off-label for MF, such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea. Ruxolitinib was intentionally excluded from this trial because the study included patients with thrombocytopenia.
Dr Mesa said the patients’ baseline characteristics “demonstrate a group of individuals with advanced myelofibrosis, a heavy percentage of those with primary myelofibrosis, the vast majority having intermediate-2 or high-risk disease, with very significant splenomegaly, and the vast majority having the JAK2 mutation.”
“About half the individuals were anemic or transfusion-dependent,” he noted. “And a full third were thrombocytopenic, under 100,000 [platelets/µL], with 16% under 50,000 [platelets/µL]. This was the first phase 3 study of myelofibrosis that allowed individuals with a platelet count of less than 100,000 to be enrolled.”
Fifty-six percent of patients remained on pacritinib at the time of analysis, as did 8% of patients on BAT. Seventy-nine percent of patients crossed over from the BAT arm to the pacritinib arm.
Spleen reduction
The study’s primary endpoint was a reduction in spleen volume of 35% or greater.
In the intent-to-treat (ITT) population, 19.1% of patients in the pacritinib arm met this endpoint, as did 4.7% of patients in the BAT arm (P=0.0003). In the evaluable population—165 patients in the pacritinib arm and 85 patients in the BAT arm—the rates were 25% and 5.9%, respectively (P=0.0001).
Dr Mesa noted that pacritinib was able to reduce spleen volume in all subgroups of patients, including those with thrombocytopenia.
“Both the group [with platelet counts] under 100,000 as well as under 50,000 uniquely responded only on the pacritinib arm, with no responses on the BAT arm,” he said.
In the ITT population, 16.7% of patients with platelet counts under 100,000/µL and 22.9% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values, in the comparison with the BAT arm, were 0.0451 and 0.0086, respectively.
In the evaluable population, 23.5% of patients with platelet counts under 100,000/µL and 33.3% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values were 0.0370 and 0.0072, respectively.
“It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation [based on the spleen responses observed],” Dr Mesa said.
TSS and transfusion
The study’s secondary endpoint was the proportion of patients with a 50% or greater reduction in Total Symptom Score (TSS) from baseline to week 24. TSS was measured by patient responses on the Myeloproliferative Neoplasm Symptom Assessment Form.
In the ITT population, 24.5% of pacritinib-treated patients and 6.5% of BAT-treated patients had a 50% or greater reduction in TSS score (P<0.0001). In the evaluable population, 40.9% and 9.9% of patients, respectively (P<0.0001), met this endpoint.
Dr Mesa also pointed out that 25.7% of pacritinib-treated patients who were severely anemic and transfusion-dependent—requiring at least 6 units of blood in the 90 days prior to study entry—became transfusion independent. But none of the BAT-treated patients did so (P<0.043).
Adverse events
“The most common adverse events [in the pacritinib arm] were consistent with the earlier studies,” Dr Mesa said. “Gastrointestinal toxicities were most common, although typically at low grades.”
“As expected, we saw very few individuals with any significant thrombocytopenia or anemia as drug-emergent. There were individuals who enrolled in the study as a grade 4, so some of those remained.”
The most common adverse events of any grade were diarrhea (53.2% in the pacritinib arm and 12.3% in the BAT arm), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).
Ten percent of patients in the pacritinib arm required dose reductions due to adverse events. Diarrhea prompted dose interruptions in 13 patients and discontinuation in 3 patients. But pacritinib-associated diarrhea typically resolved in a little over a week.
“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have an impact on the disease course,” Dr Mesa concluded.
