Considerations for JAK Inhibition for the Treatment of PV

Ruben A. Mesa, MD, FACP:The goal of therapy, simply put, is to have the polycythemia vera [PV] be as neutral in the patient’s life as possible. I judge that by trying to decrease the risk of thrombosis in bleeding, improve symptoms, improve splenomegaly if present, and hopefully use a well-tolerated therapy.

An individual who’s age 75, such as the patient we are presenting: Their risk of progression is certainly a minority. In aggregate, PV patients have about a 10% to 15% risk of progression to myelofibrosis. Certainly, time is a major factor in that equation—typically, people have the disease for 10 years or more. So I’m much more concerned about risk of progression to myelofibrosis in the 40-year-old patient who I saw with polycythemia vera than the 75-year-old individual. All that said, it certainly can occur anytime.

The goals of therapy really first start with prevention of thrombosis and bleeding. That is what we know can cause the greatest morbidity and mortality. It’s important that we always keep that foremost in our minds. But in addition to that, we want to be able to control the counts as a surrogate for decreasing that risk of blood clots or bleeding. We want to reverse disease-associated symptoms. We want to control splenomegaly if present, and certainly we need to monitor for evidence of progression.

Ruxolitinib is a JAK1 and JAK2 inhibitor. In polycythemia vera, very clearly, the overactivation of the JAK/STAT pathway is front and center in the pathogenesis of the disease. So we very much view this as an important targeted therapy that directly has an impact on decreasing that myeloproliferation, with the resulting impact being individuals becoming phlebotomy independent, having long-term control of leukocytosis and thrombocytosis, as well as seeing an improvement in the whole inflammatory milieu and improvement in symptoms, and a reduction in splenomegaly.

The clinical trials that led to the approval of ruxolitinib were the RESPONSE and RESPONSE-2 studies. In the RESPONSE trial, individuals who had failed hydroxyurea needed phlebotomies and had a splenomegaly were enrolled. Ruxolitinib was vastly superior to best alternative therapy in control of the hematocrit, symptomatic improvement, and then strong trends were seen for a decrease in thrombotic events, etc.

The RESPONSE-2 study was a confirmatory study, with the same population of people who had failed hydroxyurea who did not have splenomegaly. So really, the splenomegaly is there, it will improve, but it is not a necessary feature to really see a response.

The dosage of ruxolitinib in patients with polycythemia vera ranges from 10 mg twice a day up to 25 mg twice a day. Ten milligrams twice a day is the standard starting dosage. Indications for increasing it further would be after an adequate trial at that dosage of 3 months or 4 months, typically in my practice. If they still have difficult residual symptoms, particularly non—fatigue-related symptoms—so night sweats, severe pruritus, difficult-to-control counts such as leukocytosis or thrombocytosis, ongoing need for phlebotomies—then we would go up further on that dosing and monitor for any toxicities as they would relate, in particular, to cytopenias.

Long term, the tolerability of ruxolitinib in polycythemia vera has been excellent. As we presented the long-term data now over 5 years from the RESPONSE trial, the majority of patients continue to remain on the drug and continue to be responding and benefiting from the drug.

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