Pacritinib: New Myelofibrosis Drug, Even With Thrombocytopenia

Zosia Chustecka

May 30, 2015

CHICAGO, IL — A new drug for patients with myelofibrosis can be used even in patients with very low platelet counts, who currently have no other approved therapy. The product, pacritinib (CTI BioPharma), has completed a phase 3 trial that will be used for an approval submission.

"There is a huge unmet clinical need for patients with myelofibrosis. Only one drug is currently [approved by the US Food and Drug Administration] for the disease, and it is not safe for patients with low platelet counts," said lead study author Ruben A. Mesa, MD, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona. He was referring to ruxolitinib (Jakafi, Incyte), which, in 2011, was the first drug ever approved for myelofibrosis.

Dr Mesa presented results with pacritinib from a phase 3 study, known as PERSIST-3, here at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.

"We were encouraged to see that pacritinib was safe and effective in the trial, even in patients with severely low blood counts (<50,000/uL)," he commented in an interview. "This is the major differentiator between the two drugs," he added.

About one third of patients with myelofibrosis have low platelet counts, Dr Mesa noted, and these patients tend to have shorter survival and are at higher risk for leukemic transformations. These patients would be particularly suitable for treatment with pacritinib, but the drug showed efficacy across all subsets of patients with myelofibrosis, he noted.

Ruxolitinib is associated with a fair amount of anemia and thrombocytopenia, whereas pacritinib showed no increase in either in the study, noted study discussant Lloyd Damon, MD, professor of medicine at the University of California, San Francisco. In fact, in the study, 25% of patients receiving pacritinib could stop having transfusions for their anemia he noted. The lack of these adverse effects also allows pacritinib to be used in patients with low platelet counts, in whom ruxolitinib cannot be used or is used at a lower dose. For these reasons, Dr Damon suggested pacritinib represented an advance in the treatment of myelofibrosis.

"This is a very important agent for patients with advanced disease," Dr Damon said.

Why do the 2 drugs differ in this effect?

Pacritinib acts as an inhibitor of JAK2 and FLT3, whereas ruxolitinib acts as an inhibitor of JAK1 and JAK2, and there are also a variety of differences in the effect they have on cytokines and on the spleen, Dr Mesa explained. At the moment, it is not clear which of these differences is the most important, he said, as there are many factors that influence the low platelet counts. Laboratory studies are underway to explore the mechanisms involved, he added.

Myelofibrosis affects about 20,000 people in the United States. The disease develops when the bone marrow does not make enough normal blood cells, so the spleen takes over blood cell production and becomes enlarged, according to ASCO press materials. Patients also often experience tiredness, weakness, shortness of breath, fever, and weight loss. In about a third of patients, myelofibrosis transforms into acute leukemia.

There is currently no cure for myelofibrosis other than allogeneic hematopoietic (bone marrow) stem cell transplant, which is not a feasible option for many patients, and the only treatment approved by the US Food and Drug Administration is ruxolitinib.

Quarter of Patients Stopped Transfusions

In the PERSIST-3 trial, conducted in 327 patients with myelofibrosis, pacritinib was shown to be superior to best available therapy, which included drugs that are used off-label and commonly included the use of hydroxyurea. Ruxolitinib was intentionally excluded because this study included patients with very low platelet counts, for whom this drug is not deemed to be safe, the researchers note. In addition, patients enrolling in this trial had not been previously treated with ruxolitinib.

One of the main symptoms of myelofibrosis is spleen enlargement, which can be debilitating, as the enlarged spleen can press against other organs and cause problems with breathlessness and digestion. In this study, after 24 weeks of taking pacritinib, 19.1% of patients showed a reduction in spleen volume by 35% or more compared with 4.7% of patients receiving best available therapy (P = .0003).

A further  end-point was total symptom score, which includes night sweats, itching, bone pain, and other symptoms of the disease. The results show that patients receiving pacritinib began feeling better by 4 to 8 weeks, and at 24 weeks, half of the patients receiving pacritinib achieve a 50% reduction or more in total symptom score  compared with 9.9% receiving best available therapy (P < .0001).

Another symptom is anemia, which can be severe and require regular transfusions of red blood cells. The trial showed that a quarter (25.7%) of patients receiving pacritinib could stop having transfusions compared with none of the patients in the best available therapy group.

"This is a big deal for patients," commented Dr Mesa. "Having transfusions involves a lot of hassle, and has a big negative impact on quality of life," he said. "It takes up 2 days every fortnight, with 48 hours to receive the transfusion; then you get diuretics and you spent the night passing off the excess fluid. So it is a big deal that the drug allows some patients to stop all that."

The effects of these drugs on the patients can be "very impactful," he said. They can provide dramatic relief of symptoms, but Dr Mesa said he believes they may also prolong patients' lives, because the disease is so debilitating. About 60% to 70% of patients die from complications of the disease, pneumonia infections, and heart failure; by alleviating symptoms, these drugs make the disease les debilitating, he said. In the trial, there was a hint that the patients who saw a reduction in spleen volume may have better overall survival, but there was just a hint of this, and longer follow-up is needed.

The most common adverse effects of pacritinib were diarrhea, nausea, and vomiting. Dr Mesa said these were manageable, with antimotility agents used by some patients. The symptoms typically lasted less than 1 week, and few patients discontinued treatment because of adverse effects, the researchers noted. Three patients discontinued and 15 patients reduced the dose because of adverse effects.

This study received funding from CTI BioPharma Corp. Dr Mesa reports receiving honoraria from Novartis and research funding from Incyte, Gilead Sciences, Celgene, and CTI. Dr Damon has disclosed no relevant financial relationships (although his disclosures list some relationships with pharmaceutical companies, he said they were all his wife's; she is a cardiologist).

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA109. Presented May 30, 2015.

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