Assessing Response to Hydroxyurea Treatment

Srdan Verstovsek, MD:Our young patient was in need of cytoreductive therapy. Hydroxyurea was introduced, and the patient comes in for follow-up. After a few months, he still has uncontrolled symptoms, an uncontrolled red blood cell count, an uncontrolled white cell count—his white cell count is increasing—and abdominal symptoms from an enlarged spleen. This is a totally uncontrolled case of polycythemia vera.

To step back for a second, what is the goal of therapy? Once you introduce cytoreductive therapy, we talk about 5 different factors. First is to control the red blood cell count—a hematocrit level below 45%, which I hope everybody knows about. The second is to control the white cell count. If the white cells are increased, they should be normalized. If the platelets are increased, they should be normalized. If the spleen is increased, that should be normalized. And the symptoms should be controlled.

We usually talk about controlling polycythemia vera by looking at those 5 factors, not only red blood cell count, like in the past. In this particular case, we have no control of the symptoms and no control of the spleen, the white cell count is high, and the red blood cell count is high. This is all happening despite being treated with hydroxyurea. Plus, the patient has side effects from hydroxyurea. Leg ulcers are the most common side effect from hydroxyurea.

Side effects from hydroxyurea are not very common. Perhaps up to 10% of patients have some side effects. In 9 of 10 cases, when we talk about side effects, we see a leg ulcer, usually on a lower area of the leg, that won’t heal unless hydroxyurea is stopped. So this is a good reason to stop hydroxyurea. Even with a good control of the blood cell count, if you have side effects, that’s not satisfactory. You want to have a safe drug doing the job.

There have been a number of studies, in a retrospective way, in which patients with polycythemia vera were analyzed to see whether an elevated white blood cell count was linked to the risk for thrombosis. By and large, we all agree that this is the case. General guidelines do not currently include increasing white cell count as one of full-fledged thrombotic risk factors. It is still only age over 60 and history of thrombosis.

In our everyday practice, however, we are sensitive to increasing white blood cell count. What would make a white blood cell become accounted for in everyday, national guidelines practice? That would require a prospective randomized study with a goal of controlling the white blood cell count. That is difficult to do, but there is enough evidence to be sensitive to that number. Elevation of the blood cell count would guide one to either modify the dose to control it or, in some cases, to change the therapy.

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