Ruxolitinib as Second-Line Therapy in Polycythemia Vera


Srdan Verstovsek, MD:There are several factors that we consider as resistance to hydroxyurea. Increasing white cell count while on a stable dose of hydroxyurea with inability to increase the hydroxyurea to counteract that increase in white cell count is certainly a sign of progressive disease or a loss of control. When we talk about what the benefit of cytoreductive therapy or hydroxyurea should be, the control of red blood cells, white cells, the spleen, symptoms, and platelets should all be accounted for—5 factors. If you don’t have that and the factors are progressing while you are on hydroxyurea—the white cell count is starting to go up, you suddenly need to phlebotomize patients again, the platelets are going up and people are sensitive to that and have symptoms from too many platelets, or the spleen is progressing—these are signs of hydroxyurea failure or progressive disease. These are factors that would lead one to change therapy.

Once we determine that the patient who is on hydroxyurea needs second-line therapy, ruxolitinib comes to mind. This is approved for patients who are not doing well on hydroxyurea. The starting dose is 10 mg, given twice a day. Unlike its indication in a similar condition, myelofibrosis, where you have a different starting dose based on a patient’s platelets, here, in polycythemia vera, everybody starts at 10 mg twice a day.

Why do we start with what you would perhaps say is a lower dose? The maximum dose is 25 mg, given twice a day. We want to be safe. The expectation is that during the first 3 to 4 months, a majority of patients will need more. We analyzed this in the studies that led to its approval. Only about a third of patients stay at 10 mg twice a day. About 60% need more. They may go to 15 mg twice a day or 20 mg twice a day. There are even patients who need 25 mg twice a day. On the other hand, less than 10% of patients need less than 10 mg twice a day, which would be 5 mg twice a day. So, the expectation is that you will need more. That happens during the first 3 or 4 months, but you need to see patients more often.

Ruxolitinib was proved superior as the best available therapy in the second-line setting after hydroxyurea in all aspects that we care about when we talk about polycythemia vera—control of blood cell count, symptoms, and spleen. There is a durable result. Now that we can follow patients on the phase III randomized studies that led to its approval for much longer (4 or 5 years), we have a good understanding of its overall benefit on quality of life and blood cell count and even in decreasing the thrombotic risk that comes from the safety analysis of those studies. If you have control of the blood cell counts, you will actually control the thrombotic risk. The safety analysis of the studies showed that to be the case.

The medication is very active. It inhibits a biological problem in this condition, which is hyperactivity of the JAK/STAT pathway. This is the pathway that is inside the bone marrow cells that leads to uncontrolled cell growth. We inhibit the growth. We also inhibit inflammation that comes with polycythemia vera. That’s why people feel so much better within a month. Anti-inflammatory and antiproliferative effects are seen in a majority of patients with polycythemia vera in the second-line setting, and it’s durable and safe.

Transcript edited for clarity.

June 2016

  • A 49-year old male presents with headache, fatigue, and pain under his left ribs
  • PMH includes depression and newly diagnosed hypertension
  • Physical exam: BP, 160/90; abdominal exam reveals splenomegaly — spleen palpable 6 cm below costal margin
  • Laboratory values:
    • Hb=20.7 g/L
    • HCT= 59.4%
    • WBC=10.2x109/L
    • Platelets= 325 x109/L
  • Bone marrow biopsy:
    • MF-1 fibrosis and megakaryocytic hyperplasia with atypia
    • JAK2-positive
  • Patient was started on phlebotomy as needed and aspirin 81 mg

October 2016

  • Patient returns 4 months later with continued headache and dizziness
  • He has had 3 phlebotomies in the past 3 months
  • Patient was started on hydroxyurea 1000 mg/day

January 2017

  • Patient returns 3 months later with abdominal fullness, continued fatigue, difficulty concentrating, fever, and leg ulcer
  • Laboratory values:
    • Hb= 22.4 g/L
    • HCT= 65.3%
    • WBC=13.3x109/L
    • Platelets=153x109/L
  • Patient is started on ruxolitinib
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