Myelofibrosis – pacritinib

Myelofibrosis is a chronic, serious and life-threatening disorder of the bone marrow with a median survival of six years - and much less for very high risk patients

Myelofibrosis is a chronic, serious and life-threatening disorder of the bone marrow. It is characterised by the accumulation of malignant bone marrow cells, a process that triggers an inflammatory response, leading to scars in the bone marrow.

With bone marrow having been replaced by this scar tissue, its capability to produce new red blood cells is reduced, and this function is taken over by the liver and spleen. This causes knock-on effects in the form of the spleen becoming enlarged, along with anaemia, pain and extreme fatigue. The disease is progressive, and about a fifth of all patients with myelofibrosis will ultimately develop acute myeloid leukaemia. The median survival is about six years, but less than a quarter of this for very high risk patients.


A new potential treatment, pacritinib, is being developed by CTI BioPharma in collaboration with Baxter.1 Pacritinib is an orally available multikinase inhibitor that is active against both JAK2 and FLT3 but, importantly, not JAK1. JAK enzymes are involved in signal transduction pathways critical to the growth and development of normal blood cells, inflammatory cytokine expression and immune responses. Mutations in these enzymes are implicated in numerous haematological cancers, and while pacritinib does suppress the JAK2/STAT3 pathway, it is not myelosuppressive and thus might be effective in treating myelofibrosis while reducing the incidence of thrombocytopenia and anaemia that is commonly seen in JAK inhibitors.2

A Phase II study has been carried out in 35 myelofibrosis patients with clinical splenomegaly that was poorly controlled with standard therapies, or who were newly diagnosed with either intermediate risk or high risk disease.3 Those with thrombocytopenia, anaemia or neutropenia were all eligible for the study. Subjects were given once-daily 400mg doses of pacritinib in 28-day cycles, and the endpoint was a spleen response rate of at least a 35% reduction in spleen volume from baseline to week 24, as measured by MRI. At week 24, eight of the 26 evaluable patients had this level of spleen volume reduction, and 15 of the 31 patients had at least a 50% reduction in total symptom score.

The most common adverse events were low-grade diarrhoea and nausea, with one patient discontinuing treatment as a result. Five patients died, three as a result of serious adverse events. Anaemia and thrombocytopenia were also seen, in 12 and eight patients respectively.

Phase I studies have also been carried out in other forms of blood cancer, including a trial in 34 patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except CNS or Burkitt’s lymphoma.4 Subjects were given escalating oral doses of 100 to 600mg/day in 28 day cycles, and the response was evaluated after eight weeks. The maximum tolerated dose was not reached, and it was well tolerated, with the most common treatment related problems being gastrointestinal toxicities.

There were three partial responses at doses of at least 300mg/day, and 15 patients achieved stable disease, about half of whom had tumour reductions. Most responses lasted at least two months.


1. A.D William et al. J. Med. Chem. 2011, 54, 4638

2. S. Hart et al. Blood Cancer J. 2011, 1(11), e44

3. R.S. Komrokji Blood, 2015, Mar 11, pii: blood-2013-02-484832, epub ahead of print

4. A. Younes et al. J. Clin. Oncol. 2012, 30, 4161