The Role of Ruxolitinib in Treating Polycythemia Vera

Prithviraj Bose, MD:There were 2 trials, phase III randomized trials, RESPONSE and RESPONSE-2, which evaluated ruxolitinib against best available therapy in patients who were resistant or intolerant to hydroxyurea. The difference between the 2 studies, which were otherwise pretty identically designed, was that in RESPONSE, patients had to have splenomegaly, and in RESPONSE-2, they did not have splenomegaly. I pointed out earlier that splenomegaly is not particularly common in PV [polycythemia vera], so it was nice that we had 2 randomized trials looking at both these populations with and without splenomegaly.

In both trials, the primary endpoint was actually a composite. Well, actually, let me rephrase that. In RESPONSE, it was a composite of hematocrit control and spleen volume reduction at week 32. And ruxolitinib beat the best available therapy. I want to say that the numbers were about 23% versus somewhere in the range of 1% for the composite outcome, which was again a combination of hematocrit control and spleen volume reduction. If you looked at all the individual endpoints, ruxolitinib again beat the best available therapy separately for hematocrit control, for spleen volume reduction, for total symptom score reduction, and for the percentage of patients who attained a complete hematologic response [CHR].

The same—or I should say very similar—results were found in RESPONSE-2, which was the trial done in patients without splenomegaly. Obviously, the primary endpoint there was just 1 thing, which was hematocrit control, because spleen volume reduction was not relevant. But the symptom control, the CHR attainment, all of this was clearly superior, significantly superior for ruxolitinib. Obviously, an important outcome is thrombosis prevention, and this outcome also favored ruxolitinib, although not statistically significantly, but there was a clear trend in favor of ruxolitinib, in favor of the ruxolitinib arm for reduction of thromboembolic events.

I start all patients with PV who I start on rux [ruxolitinib] at 10 mg twice daily. I emphasize the importance of taking it twice daily because of the half-life of the drug. It’s important not to take it once daily. Then I go up as needed. So what I mean by that is, again, I don’t know that there are easy rules to recommend here. I think one has to look at obviously the hematocrit because the primary goal of whatever you do in PV or everything you do in PV is to keep the hematocrit under 45%. That is pretty much set in stone, based on the CYTO-PV trial. So that is my first goal, but then once that is attained, I may still titrate up the dose if the symptoms are not controlled or let’s say the white blood cell count is not controlled. Because we know, increasingly now that the white count blood cell is implicated in thrombotic risk. In fact, the CYTO-PV trial is 1 of the trials that showed that as well as symptoms. So we know from myelofibrosis, for example, that 25 mg twice daily is the max dosage. So I’ll go up as needed.

I will say that I don’t have patients on rux [ruxolitinib] who are that far out. Again, the drug was approved in December 2014, so as you can see, it really has not been that long. I have not had issues with rux [ruxolitinib] safety in any of my patients with PV. As I said, a rare issue that one can encounter, which I have in the myelofibrosis setting, is the nonmelanoma skin cancer. I will say, I will point out that rux [ruxolitinib] does increase your risk for shingles. This was seen in the RESPONSE trial. It seemed fairly clear that the rux [ruxolitinib] arm had a higher incidence of shingles. What I do now is I vaccinate all patients on rux [ruxolitinib] with Shingrix, which is this new killed or inactivated shingles vaccine. So I will put that out there. It is something the NCCN [National Comprehensive Cancer Network] Guidelines also recommend.

Transcript edited for clarity.

Case: 58-Year-Old Woman Diagnosed With Polycythemia Vera

November 2018

• A 58-year old woman presents to PCP complaining of abdominal pain, dizziness and headaches
• PE: BP 140/85; Splenomegaly ~6 cm below left costal margin
• PMH: No prior history of thrombosis
• Lab values:
  • HGB: 17.1 g/dL
  • Hct: .50 L/L
  • RBC: 71 x 10¹²/L
  • WBC: 13.2 x 10⁹/L
  • Serum EPO: 4.1 mU/mL
• Bone Marrow Biopsy: Erythroid hyperplasia
• Cytogenetics: JAK-V617Fmutation