Novel JAK Inhibitor Reduces Spleen Volume and Symptoms in Myelofibrosis


Compared with best available therapy, the novel JAK2 inhibitor pacritinib demonstrated significantly better outcomes in spleen volume reduction and symptom control when administered to patients with myelofibrosis.

Ruben A. Mesa, MD

Ruben A. Mesa, MD

Compared with best available therapy, the novel JAK2 inhibitor pacritinib demonstrated significantly better outcomes in spleen volume reduction and symptom control when administered to patients with myelofibrosis; a population that often struggles with low platelet counts and few therapeutic options.

In the phase III PERSIST-1 study,1pacritinib reduced spleen volume by ≥35% for 19.1% of the intent-to-treat (ITT) population who received the drug compared with the 4.7% who achieved that reduction on best available therapy (P= .0003) at the 24-week mark, said lead investigator Ruben A. Mesa, MD, during a press briefing at the 2015 ASCO Annual Meeting. Additionally, 40.9% of the evaluable population who received pacritinib achieved a ≥50% reduction in total symptom score at 24 weeks using the Myeloproliferative Neoplasm Symptom Assessment, compared with 9.9% among those in the control group (P= .0001).

Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona, said the benefits of pacritinib were evident among patients regardless of their platelet levels. However, he said the findings are particularly meaningful for those with platelet levels of <50,000/&mu;L.

Patients in this group are not candidates for ruxolitinib (Jakafi), which became the first JAK inhibitor and the first drug specifically approved for patients with myelofibrosis in 2011. The FDA has approved ruxolitinib for patients with intermediate- or high-risk myelofibrosis, with dosing linked to platelet counts starting at 50,000/&mu;L (50 x 109/L to <100 x 109/L).2

Twenty-five percent of patients with myelofibrosis have platelet levels below this threshold at the time of diagnosis, and the incidence rises to the 30% to 50% range as patients undergo therapy, Mesa said. &ldquo;As early as 1 year from the time of diagnosis, the incidence of disease-related thrombocytopenia, anemia, and red blood cell transfusion requirements increases dramatically,&rdquo; Mesa said.

A rare cancer, myelofibrosis affects approximately 20,000 people in the United States, according to statistics cited by ASCO.

&ldquo;At this point, under 50,000 there are no approved therapies,&rdquo; said Mesa. &ldquo;There will be off-label use of therapies, even off-label use of ruxolitinib,&rdquo; but at lower dose levels that might impair its efficacy.

&ldquo;The goal is to have an impact on the disease by reducing splenomegaly and symptoms,&rdquo; Mesa said. &ldquo;We believe that as a class the JAK inhibitors likely have an impact upon survival, probably by decreasing the morbidity of the disease. Many patients with myelofibrosis really die of complications related to the disease such as pneumonia or heart failure—they develop thrombosis. That debilitation, when it&rsquo;s reversed, we think is impactful in terms of their outcomes.&rdquo;

Research into pacritinib is continuing with the phase III PERSIST-2 trial, which is evaluating the drug in comparison with best available therapy that may include ruxolitinib among patients with myelofibrosis with platelet counts &le;100,000/&mu;L, according to CTI BioPharma, the Seattle-based company developing the agent.3

Key Outcomes in Trial

In the PERSIST-1 trial, 327 patients were randomized 2:1 to receive 400 mg pacritinib daily versus physician&rsquo;s choice of best available therapy excluding prior ruxolitinib. Hydroxycarbamide (55.7%) and a watch-and-wait strategy (25.5%) were the most prevalent approaches in the control arm.

Patients with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythema-myelofibrosis were eligible to enroll. There was no required platelet level for enrollment; 32% had platelet levels <100,000/&mu;L and 15% had counts <50,000/&mu;L.

Pacritinib demonstrated superior outcomes in every measure. The primary endpoint of spleen volume reduction &ge;35% was achieved not only in the ITT population, but also among evaluable patients. (The ITT population consisted of 220 patients who received pacritinib and 107 who were given best available therapy).

Among evaluable patients, 25% of participants who received pacritinib (n = 168) reached the spleen volume reduction threshold, versus 5.9% of the best available therapy arm (n = 85) (P= .0001).

The differences were even more pronounced for patients with baseline thrombocytopenia. Among this group, the percentages of patients with <50,000/&mu;L platelets who achieved spleen volume reduction &ge;35% were 22.9% and 33.3% for the ITT and evaluable populations, respectively. For those patients with baseline thrombocytopenia and <100,000/&mu;L platelets, 16.7% and 23.5% achieved spleen volume reduction &ge;35% in the ITT and evaluable groups, respectively.

Notably, the rates of spleen volume reduction correlated with overall survival, with patients who received pacritinib experiencing greater benefits, Mesa indicated. Among patients who were dependent upon red blood cell transfusions, 25.7% of those who received pacritinib became independent during the trial, while none of those on best available therapy reached this milestone (P= .043), according to the conference abstract.

The abstract also reported that the most common adverse events (AEs) for pacritinib were diarrhea, nausea, and vomiting, with a low incidence of grade 3 severity AEs.

&ldquo;Based on preliminary data, pacritinib may be disease modifying and warrants combination studies with other potentially disease-modifying agents in myeloproliferative neoplasms,&rdquo; Mesa said.


Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract LBA7006.

Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2104.

Persist 2. CTI BioPhama Corp website. Accessed May 30, 2015.

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