A Case of Hydroxyurea Intolerant Polycythemia Vera - Episode 2

Considerations for Starting Cytoreductive Therapy in PV

Ruben Mesa, MD:As we’re following this patient, they are continuing to need phlebotomies, they’re continuing to have symptoms. So, the individual really is not adequately controlled with the phlebotomy and aspirin. And to some degree, that’s not a surprise. This individual presented with a fairly aggressive portfolio of counts and symptoms, and is appropriately started on hydroxyurea at 1000 mg a day. But see, the goals of that include several things. Can we decrease that rate of phlebotomies, or get an individual to really where it is just the rare occasional phlebotomy? I don’t know whether it’s necessary for a patient to have zero phlebotomies, but over time, I think they should really be infrequent. Otherwise, to some degree, it’s a sign of overly active disease.

The advantage of medical therapy with cytoreduction with hydroxyurea includes not having to make the patient be as severely iron deficient. Phlebotomy really is iatrogenic iron deficiency. That’s the only reason it helps to control the counts. And like any other therapy, iatrogenic iron deficiency is quite valuable as to how well a patient tolerates that component.

Now, a limiter of iatrogenic iron deficiency as the therapeutic goal is that it frequently is disappointing for controlling splenomegaly or certain symptoms, and sometimes we’ll exacerbate other symptoms by adding to fatigue, restless leg, or other difficulties that can arise.

This individual, I would say, again, remains more in that intermediate-risk category. They have cardiovascular risk factors. They are under age 60. They’ve not had a thrombotic event, but they are highly symptomatic and they are not tolerating phlebotomies well. So, intermediate would be very consistent with our current NCCN guidelines for consideration of cytoreductive therapy.

The decision on when to make hydroxyurea, or cytoreduction, part of the therapy includes the dynamic monitoring of the patient. The historical way that polycythemia vera was managed, which was solely the initiation of cytoreduction on the basis of being high risk, I think was really inadequate. That historical “high risk” had to do with what was your risk of developing a thrombotic event? It did not correlate with how well you felt with the disease, how well the disease was controlled, or how much the patient was suffering with the disease. So, I think it really was a very partial view of the burden the patient was facing. It was in that spirit that our current NCCN guidelines viewed that low- and intermediate-risk patients may, too, benefit from cytoreductive therapy in certain circumstances. And that can be not tolerating phlebotomies well. Or, having difficult symptoms. Or, having difficulties with splenomegaly, some of which all are presented in the case that we have before us.

Now when we begin hydroxyurea therapy, as I share with patients, most patients with polycythemia vera who are managed with hydroxyurea are between 10 to 20 pills a week—7 pills are 1 a day, 14 pills a week is 2 a day, 21 pills are 3 a day. So, most are somewhere in that 2- to 3-pill range per day. And starting a patient, as this one was, at 2 pills a day is a fairly reasonable starting place, particularly for a 49-year-old individual. If an individual is very elderly, or if they have a very modest body weight, then I might start at a little lower dose of 1 a day.

Monitoring ongoing hydroxyurea use in a patient with polycythemia vera, I’m looking at several things. One is hydroxyurea primarily helps to control the counts. So, first, that is the main driver. Am I getting them to need less phlebotomies or very few phlebotomies? They have leukocytosis or thrombocytosis, am I able to normalize those consistent with the ELN response criteria? If their splenomegaly doesn’t reduce, if they have symptoms, particularly symptoms associated with higher counts, are they improved? Those are, in part, drivers of, should I be increasing the dose if I’m not achieving those goals, up to a maximum tolerated dose of 2000 mg a day?

I’m also monitoring for toxicities as they go up on the dose. Am I achieving neutropenia, which would be a dose-limiting toxicity? Am I having cutaneous toxicities in the mouth or skin or on the legs, nausea, or other limiting toxicities?

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