ASCO 2015

Novel JAK inhibitor pacritinib proving effective for easing symptoms of myelofibrosis

Dr Ruben Mesa - Mayo Clinic Cancer Center, Scottsdale, USA

Can you explain to me why you were looking at myelofibrosis? What was the big deal here because it’s a disease that’s not that easy to treat, what did you think you could do for it?

Myelofibrosis is a difficult chronic myeloid neoplasm that can lead to significant morbidity through splenomegaly severe symptoms and cytopenias. It clearly can lead to mortality by that morbidity as well as progression to acute myeloid leukaemia. Our goal was really to see if we could alleviate the suffering of these patients with myelofibrosis.

And to do that investigationally you were using pacritinib, what is pacritinib?

Pacritinib is a FLT3 and JAK2 inhibitor, the JAK-STAT pathway has been found to be integrally involved with the development of myelofibrosis and in early studies had demonstrated an ability to improve splenomegaly and symptoms but had a unique characteristic in that it seemed to potentially improve baseline cytopenias as well as not cause any drug emergent cytopenias.

You were using splenic reduction as the primary endpoint, weren’t you, why?

As we’ve tried to evaluate myelofibrosis there are international guidelines for response of which reduction in splenomegaly is felt to be an important biomarker of the disease, one to alleviate the suffering that comes with sometimes massive splenomegaly these patients can have. There are times their spleen can be over ten times its normal size, so that can create pain, discomfort, early satiety and a variety of morbidity. But also it seems to correlate well with activity against the disease.

And you can have a primary myelofibrosis or it can follow polycythemia vera or ET. What’s the difference in those different cases?

There might be slight differences between those three groups in terms of their pathophysiology, how they evolve, but they evolve to a final common endpoint or status in that the clinical burden of the disease, regardless of which group you’re in, seems to be similar in terms of significant splenomegaly, morbidity as well as difficult symptoms.

So what did you do?

We performed a phase III study randomised two to one between pacritinb 400mg/day versus best alternative therapy in a little over 300 patients in an international study. We identified that pacritinib was vastly superior to best alternative therapy for individuals who were enrolled in the study, including individuals who had very significant thrombocytopenia, which was a unique characteristic compared to other studies that have been performed for myelofibrosis.

And just for the record, what typically was best alternative therapy?

Best alternative therapy, since there is no approved therapy in that group, 25% were really just supportive care, others included hydroxyurea or a variety of different oral agents largely used off label as there’s no approved therapy in that group.

What are the clinical benefits, then, coming out of your apparently successful treatment?

The clinical benefits were specifically reduction in splenomegaly, the primary endpoint, which was very significant in favour of pacritinib, in particular in those individuals with baseline thrombocytopenia who would otherwise have no other treatment options. We observed 25% of patients who were red cell transfusion dependent became transfusion independent, which was a very important finding. Finally we observed that there was a very significant improvement in myelofibrosis related symptoms.

What do you regard as the clinical implications of those findings?

I think in particular it opens up a new therapy for individuals with significant cytopenias with myelofibrosis who, at the moment, have no good treatment options and no approved treatment options in either Europe or the US.

Was there a downside to this?

In terms of toxicities there can be low grade GI toxicities, diarrhoea most prevalent and nausea and vomiting in a small percentage, typically manageable by antidiarrheals and not a limiting characteristic but that was the main side effect.

So what’s your take home for doctors?

I think it will be a very important new therapy for patients with myelofibrosis, in particular for those with very low counts, potentially those who are transfusion dependent for red cells as well as those with thrombocytopenia. So I think individuals will welcome having potentially another agent at their disposal for treating these patients.