The Use of Ruxolitinib in MPN

Rami Komrokji, MD:As our audience knows, ruxolitinib has been instrumental in the management of myelofibrosis patients. Can you briefly summarize to us the data with the COMFORT studies and the use of ruxolitinib for myelofibrosis?

Prithviraj Bose, MD:Sure, absolutely. RUX, as we normally abbreviate ruxolitinib, was FDA approved first in 2011 based on the COMFORT-I and COMFORT-II phase III trials, as you alluded to. COMFORT-I was a placebo-controlled trial, mainly conducted in North America and Australia. COMFORT-II was a phase III trial comparing RUX [ruxolitinib] with best available therapy, mainly in Europe. For both of these trials, the primary end points were 35% spleen volume reduction by imaging and then also symptom improvement by different assessment tools. For example, COMFORT-I used the Myelofibrosis Symptom Assessment Form, and I believe the COMFORT-II used some other indices of symptom improvement.

In both of these trials, ruxolitinib was clearly statistically significantly superior to placebo or best available therapy for both those end points. As examples, in COMFORT-I, at 24 weeks you had about a 42% spleen volume reduction rate with ruxolitinib, and a similar rate in reduction of symptoms as well. For symptoms, there’s usually a 50% reduction in the total symptom score. It was clearly superior in both trials, and that’s what got the drug approved. Important to mention, these patients were intermediate-2 or high-risk patients with myelofibrosis, so a little more advanced phase of the disease. Also, their platelets had to be 100,000 or higher.

Rami Komrokji, MD:Absolutely. Where do you initiate the treatment for those patients? Which are the patients that you select for the ruxolitinib, and when do you start the treatment? Do you include the patients with intermediate-1 as well?

Prithviraj Bose, MD:We have learned a lot since the COMFORT trials. There has been extensive experience in intermediate-1 as well, as you just alluded to. There were trials called the ROBUST trial and the JUMP trial that included a large number of intermediate-1 patients. So yes, I am comfortable using it in those patients. I typically do not use it in low-risk patients. However, if a low-risk patient is symptomatic, then I will use it, and this is endorsed by NCCN [National Comprehensive Cancer Network] as well.

We also learned a lot about how to use it in the face of cytopenias. Per the package insert you are not to use it with platelet counts less than 50 mm³. But for the most part, physicians have gotten comfortable with doing even that at low doses. And then the other thing you see is anemia. There was actually an abstract this year at the EHA [European Hematology Association Congress] in June called the REALISE trial, in which patients who had a hemoglobin of less than 10 g/dL could start at a lower dose. As you know, typically we dose ruxolitinib according to the platelet count. But in these anemic patients, they started with 10 mg twice a day. After 12 weeks they went up, and that was a successful strategy as well.

Rami Komrokji, MD:I think my practice is similar. Obviously, patients who have splenomegaly and constitutional symptoms, I think those are the patients who benefit from it. Both of the studies, the COMFORT alluded to it, were not designed to look at overall survival. But both of them had a signal of improved survival. I tell the patients this is a treatment for symptoms, but patients’ performance improves, their symptoms get much better, and they do drive survival advantage indirectly probably from the treatment. As you mentioned, I think one has to be aware of the cytopenias and the management. If I’m in doubt, for borderline cytopenias, I start with a lower dose but try to escalate fast. I discuss with patients that maybe the symptom improvements are going to be seen very quickly, within 1 to 2 weeks with even a low dose, while spleen response is a little more dose dependent and needs more time to achieve. But there is no doubt that it had changed the management for patients and that improvement that we see from the treatment for patients had been instrumental for further management.

Prithviraj Bose, MD:Absolutely. That survival benefit is very well established. It’s now in the label, and as you rightly point out, it is dependent on the spleen response. So you do need to optimize the dose to get the best spleen response.

Transcript edited for clarity.