Data on Two New Therapies Offer Hope for Myelofibrosis Therapy

By Annette M. Boyle, contributor.

Save to PDF Clinical TrialsOncologyEvidence-Based MedicinePerformance-Based Medicine By
  • Data from ASH and ASCO offer new hope for patients with myelofibrosis.
  • Two new oral multikinase inhibitors mark significant advances.
  • Pacritinib and ruxolitinib demonstrated ability to reduce spleen volume by >35%.
  • Data from PERSIST and COMFORT trials are promising.

Research presented at the most recent annual meetings of the American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) offers good news for patients with myelofibrosis (MF) and the physicians who care for them. Promising data were presented for 2 new oral multikinase inhibitors Both pacritinib and ruxolitinib demonstrated ability to reduce spleen volume by 35% or more, among other advantages.(Figure 1.)

Figure 1. A scanning electron microscope image of normal circulating human blood.
In addition to the irregularly shaped leukocytes, both red blood cells
and many small disc-shaped platelets are visible.
(Sources: Wikipedia/By Bruce Wetzel (photographer). Harry Schaefer (photographer) 
Image and description: National Cancer Institute/Public Domain

Pacritinib is an oral multikinase inhibitor that targets JAK2, FLT3, IRAK1 and CSF1R, all of which play key roles in the development and progression of myelofibrosis and other blood-related malignancies. Of patients evaluable at baseline and at 24 weeks, 25% of those receiving 400mg pacritinib daily achieved 35% or greater spleen volume reduction compared to 5.9% of those receiving a non-JAK (Figure 2) inhibitor best available treatment.

The subgroup analysis of the PERSIST-1 trial, presented at the ASH meeting, showed consistent spleen volume reduction irrespective of baseline risk factors including platelet count, sex, age, JAK2-mutation status, baseline MF diagnosis of primary versus secondary MF, reticulin and collagen fibrosis staging, white blood cell count, peripheral blasts, transfusion dependence, or bone pain.1

Figure 2. Structure of the JAK2 protein.
(Sources: Wikipedia/Creative Commons/By Emw - Own work.)

The most notable reduction in spleen volume (>21%) compared to best available treatment was seen in patients with baseline platelet levels of <50,000/μL, in JAK2V617F-negative patients, and those aged <65 years. Patients (84% at 27 weeks) who crossed over to pacritinib from the best available treatment arm achieved similar spleen-volume reduction.

Pacritinib is the first investigational agent shown to be effective for patients with thrombocytopenia.2 Notably, a quarter of patients receiving pacritinib achieved transfusion independence compared to none in the best available treatment group.3

Patients also consistently achieved a reduction of ≥50% in total symptom scale (TSS) across all subgroups, a significant achievement for a patient population burdened by multiple symptoms that markedly reduce quality of life. Gastrointestinal adverse events affected the majority of patients, but generally resolved within 2 weeks.

In February, the FDA placed a full clinical hold on pacritinib based on detrimental effects to patients in terms of overall survival as a result of intracranial hemorrhage, cardiac failure, and cardiac arrest. In March, the FDA expressed interest in permitting patients who were receiving benefit from pacritinib to apply for Single Patient IND. As many as 416 patients could appeal for SPI. The FDA also recommended dose-exploration studies.

The PERSIST-1 Trial

Studies presented recently at the annual ASCO meeting analyzed 72 weeks of results for all patients in the PERSIST-1 trial and found durable spleen volume reduction and no statistically significant difference in overall survival between pacritinib and best available treatment, except that those receiving the investigational drug. These patients experienced >20% reduction in spleen volume and longer overall survival.4 The incidence of all-grade cardiac adverse events was similar in patients in the 2 arms up to week 24; it was higher in the pacritinib arm after week 24, but still lower than 5%. Among all patients, the incidence of grade 3/4 bleeding events did not exceed 3%.


Positive results were reported at recent conferences for another drug used to treat MF. Ruxolitinib gained FDA approval for treatment of patients with MF in 2011 based on results from the COMFORT-I and II trials. It was also approved in 2104 for treatment of patients with polycythemia vera.  The most recent study on ruxolitinib found that the benefits achieved in the initial research, including reduced spleen size and improved overall survival, continued with long-term therapy. Both safety and tolerability profiles remained unchanged over a 5-year period.

Ruxolitinib is a potent JAK1/JAK2 inhibitor shown to rapidly reduce splenomegaly and associated symptoms and to improve survival in patients with myelofibrosis. The COMFORT-II trial was a randomized, open-label Phase III study of ruxolitinib (n=146) versus best available therapy (n=73) in patients who had intermediate-2 MF, high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia (Figure 3.) MF. Patients were allowed to crossover from the best available therapy arm if they had ≥25% increase in spleen volume. All patients in the best available therapy arm had discontinued or crossed over as of November 2011. The study continued until April 20, 2015.


In the COMFORT-II trial, 28% of patients receiving ruxolitinib achieved the primary endpoint of ≥35% decrease in spleen volume from baseline to week 48. None of the patients receiving best available therapy achieved this endpoint. Spleen volume reductions persisted at 3-year followup and patients tolerated long-term treatment.

The ASH presentation, subsequently published in Leukemia, discussed results from a 5-year final follow up to COMFORT-II.5,6 At the completion of the study, 39 patients (26.7%) in the ruxolitinib arm and 11 of the 45 patients who crossed over from the other arm remained. Patients in the ruxolitinib group discontinued primarily because of adverse events (24%) and disease progression (21.9%), while those receiving best available treatment withdrew consent (12.3%) or discontinued for other reasons (12.3%).


Figure 3. Thrombcytopenia.
(Sources: Wikipedia/Creative Commons/By Prof. Erhabor Osaro - Own work.)

During the course of the study, 78 patients (53.4%) in the ruxolitinib arm experienced a ≥35% reduction in spleen volume at some point. Spleen volume reduction persisted on average for 3.2 years.

Among evaluable JAK2-V617F-positive patients, 38% had ≥20% reduction in allele burden at 3.2 years. Nearly 1 in 3 maintained that reduction at 3.7 years. Fibrosis improved in 23 of the ruxolitinib patients, with 4 improving to grade 0. Another 47 (32.2%) had stable fibrosis and in 27 (18.5%) fibrosis worsened by the final assessment.

Longer treatment time was not associated with an increase in adverse events. Adverse events associated with ruxolitinib at any point in the study included thrombocytopenia (52.4%), anemia (49.2%), diarrhea (35.6%), and peripheral edema (33.0%). The grade 3/4 adverse events included anemia (22.5%), thrombocytopenia (15.2%), pneumonia (5.8%), general physical health deterioration (4.2%) and dyspnea (4.2%). Leukemia developed in 8 patients (5.5%) in patients in the ruxolitinib arm and in 5 patients (6.8%) receiving best available treatment.

Among patients in the ruxolitinib arm 59 died (40.4%). Median overall survival for the group was not reached during the 5 years of the study. By comparison, 35 patients in the best available treatment arm died (47.9%), and the median overall survival of among these patients reached 4.1 years. The risk of death declined by 33% on ruxolitinib, though the extensive crossover of patients led to some confounding in this part of the analysis.


  1. Vannucchi AM, Mesa RA, Cervantes F, Prasad R, et al. Analysis of Outcomes by Patient Subgroups in Patients with Myelofibrosis Treated with Pacritinib vs. Best Available Therapy in the Phase III PERSIST-1 Trial. ASH 2015.
  2. Mesa, R, et al. Pacritinib vs. best available therapy in myelofibrosis: 60-week follow-up of the Phase III PERISIST-1 trial. Abstract #7065. ASCO 2016.
  3. Harrison, C, et al. Pacritinib vs. best available therapy in myelofibrosis: Outcomes in patients with baseline thrombocytopenia. Abstract #7011. ASCO 2016.
  4. Harrison, C, et al. Outcomes in patients with myelofibrosis and RBC-transfusion dependence in the phase III PERSIST-1 study of pacritinib vs. best available therapy. Abstract #7066. ASCO 2016.
  5. Mesa, R, et al. Pacritinib vs. best available therapy in myelofibrosis: Long-term follow-up of patient-reported outcomes in the phase III PERSIST-1 trial. Abstract #7067. ASCO 2016.
  6. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-Term Findings from COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy for the Treatment of Myelofibrosis. Leukemia. 2016 Jun 17.