The RESPONSE trial is a phase III prospective randomised trial in patients with polycythaemia vera but specifically in the category of patients with polycythaemia vera who become intolerant of or are refractory to the most commonly used cytotoxic drugs for the management of the disease, that is hydroxyurea. So in these patients the RESPONSE trial assesses the efficacy, and the safety of course, of ruxolitinib that is a JAK1 and JAK2 inhibitor against best available therapy with the objective to control haematocrit and to reduce the spleen.

Is this the best available therapy including phlebotomy?

In this category of patients that are considered at high risk polycythaemia vera, according to the current guidelines, you are suggested to use not only phlebotomies but cytotoxic drugs because these patients are at very high risk of developing thrombotic events. In addition, most of these patients that are refractory to conventional treatment have an advanced form of polycythaemia vera so phlebotomy alone is not enough.

What is it ruxolitinib does?

In this study we had evidence that ruxolitinib was able to produce a control of the measure endpoints of the study, that was a composite endpoint, that means the proportion of patients who obtained the target control of haematocrit, that means less than 45% in the absence of phlebotomies and reduction in the spleen volume of at least 35% from baseline at week 32. We found that the proportion of patients in the ruxolitinib arm who obtained the composite primary endpoint was 21% as compared to 1% in the best available therapy.

What is the mechanism?

The mechanism is very closely associated with polycythaemia vera and its mutational status. Because we know that almost 100% of patients with polycythaemia vera have a mutation in this gene that is called JAK2 and these mutations make the protein, the JAK2 protein, to be continuously active rather than being regulated. Therefore the haematopoietic cells of these patients are able to go up without the normal control of growth factors. Therefore, the activation of JAK2 results in an over-activation of the cells, the signalling within the cells, and ruxolitinib being able to target the activated JAK2 protein stops this abnormal proliferation of the cells.

You met the primary end point in three-quarters of the patients?

Yes, it was a good result but particularly you have to also consider that 77% of the patients in the ruxolitinib arm obtained at least one of the two major components of the primary endpoint. That means that 60% of the patients in the ruxolitinib arm were able to obtain the target control of haematocrit in the absence of phlebotomy as compared to 20% in the best available therapy group. Also 38% of ruxolitinib treated patients, as compared to only 1%, obtained a reduction in the spleen volume.

What about adverse events?

The therapy was really well tolerated and if you consider the rate of adverse events for year of treatment this was half in the group of ruxolitinib as compared to best available therapy. In particular there were no novel adverse events as compared to what has come out from the COMFORT-1 and COMFORT-2 studies that are the two phase III studies that led to the approval of ruxolitinib for the treatment of myelofibrosis. So no new signal.

Were symptoms improved?

This was one of the additional endpoints of the study. The additional endpoint was to measure the proportion of patients who had benefits from ruxolitinib in terms of symptoms that are associated with the disorders. Almost 50% of patients in the ruxolitinib arm, as compared to 5% in the best available therapy group, were able to show an improvement in the symptoms.

What are the clinical implications of this study?

The clinical implications, I think, are important for the selected category of patients because we have to stress again that this study was done in patients with polycythaemia vera, high risk patients, who were refractory or intolerant of hydroxyurea. So in these patients that represent an unmet therapeutic need in the field I think that ruxolitinib really may represent a new option for treating these patients. We also have to mention that one additional finding, in my opinion a very important finding, from this study was that the rate of thrombotic events was lower in patients randomised to ruxolitinib, only one event as compared to six events in the best available therapy group. So this really opens new avenues for the use of this agent in the treatment of patients with polycythaemia vera.