Treating PV With JAK Inhibition Now and in the Future

Ruben A. Mesa, MD, FACP:My real-world experience with ruxolitinib in polycythemia vera [PV] has been very consistent with the data that we presented in The RESPONSE trial. The agent is effective. People feel better on the drug. It helps to control their disease. These are people who’ve already failed hydroxyurea. They have good control of the disease. They become phlebotomy independent. They have improvements in symptoms. And yes, if they had enlargement of the spleen, it certainly helps to improve that enlargement of the spleen.

Now from the dose, again, the majority are able to remain on 10 mg twice a day, with a few needing a higher dose for control of leukocytosis or refractory pruritus or things of that nature.

I do find that that risk of herpes-shingles is a little higher than in the general population. It’s probably less than 10% of people, but I am mindful of that. In particular now, since we have the inactivated herpes-shingles vaccine, we have been utilizing that in patients. There’s not a clinical trial to approve that for this group of patients. However, it’s a safe and effective vaccine, so it is a reasonable consideration for these patients.

Finally, I do think that all MPN [myeloproliferative neoplasm] patients have a higher risk of nonmelanoma skin cancers. I think the JAK inhibitor era has just made us more aware of that fact. It’s higher at baseline, and it’s higher with therapy. So I am mindful of those skin-related issues and do involve a dermatologist as part of the patient’s care team, particularly if they’re older, to be mindful for any premalignant lesions or any squamous cell carcinomas, etc, if they occur.

Ruxolitinib was tested first in the second-line setting. Because of an unmet medical need, it was a logical place to begin. Ruxolitinib undoubtedly will be active in the frontline setting and will be beneficial in a range of ways. What the indications will be for that utilization in the frontline setting will need to be supported by a clinical trial. Obviously, there are health economic discussions and in which patients that would be appropriate. I think most likely what will evolve is we will have a better understanding of risk, disease burden, and risk of progression. I think it will become an option as frontline therapy for PV. Maybe not universally, but I suspect that we will find subsets in which it is an appropriate consideration in the frontline setting.

The unmet medical needs in PV begin with our gap in the understanding of why patients progress. Indeed, if I had 100 patients with PV in front of me at the time of diagnosis, we know that there’s a subset who are going to progress to more aggressive, advanced disease. If we were to understand why they progress, how we can monitor that, how we help to prevent that from recurring, we would want to approach the disease differently. Maybe those individuals should start on ruxolitinib? Maybe they should be on ruxolitinib with interferon? They have complementary mechanisms of action. Maybe that’s a possibility. Maybe that’s dramatic overkill in somebody else with polycythemia vera who might be easily controlled with phlebotomy and aspirin and/or hydroxyurea? I think it’s still a heterogeneous group. So that biological knowledge gap remains an important gap.

Secondly, in terms of therapies, we still do not have perfect clarity on this issue of hydroxyurea versus interferon. I think more data will help us really sort that out. Should hydroxyurea really evolve away from being our frontline option? Could there be more discussion of interferon and ruxolitinib? Certainly, many of my other MPN-focused colleagues and I view that those are clearly the 2 best agents we have in polycythemia vera, and hydroxyurea is probably a more distant agent as a nonspecific agent.

There clearly are other therapies in development, looking at everything from nutlin inhibitors and others that may have activity in this group of patients. All of that is slow in development but may potentially play a role as well.

Transcript edited for clarity.

Case: 75-Year-Old Man Diagnosed With Polycythemia Vera

January 2018

• A 75-year old man presents to PCP for routine evaluation; feels well but complains of pruritus exacerbated by hot showers
• PE: Unremarkable
• PMH: No prior history of thrombosis, hypertension managed with statin
• Lab values:
  • HGB: 18.9 g/dL
  • Hct: .56 L/L
  • RBC: 68 x 10¹²/L
  • WBC: 10.6 x 10⁹/L
  • Serum EPO: 4.1 mU/mL
• Bone Marrow biopsy declined
• Cytogenetics: JAK-V617Fmutation