A Case of Hydroxyurea-Intolerant Polycythemia Vera


Ruben Mesa, MD:So, this is an individual who clearly has difficult polycythemia vera, which is active and has some features to give me greater concern that they have an eventual risk for progressing toward myelofibrosis. They clearly are quite symptomatic, present with symptoms really related to very high counts—has headache and fatigue, has splenomegaly on exam but has symptoms from the splenomegaly, so really an active disease.

This individual has hypertension. That might be essential but it certainly might be related to very elevated set accounts. They present with a hematocrit of almost 60, so that is an individual who we know is at high risk, and even in immediate or high risk of needing an important and urgent therapy. They have some leukocytosis. They have theJAK2mutation, that clearly is to be expected. Their bone marrow shows some changes suggestive that they might eventually progress to myelofibrosis. This individual clearly does not meet the criteria of having myelofibrosis at this juncture. They clearly have polycythemia vera. But individuals on that spectrum live on a broad spectrum for being very far away from post-PV myelofibrosis to being walking along that path. And this would suggest this is probably an individual who has had polycythemia vera for a while and it has not been recognized, and too clearly has higher-risk disease and is well along that more difficult path.

Diagnosing polycythemia vera in 2018 utilizes the 2016 WHO criteria, which include clear elevation and unexpected increase in the counts, particularly around the hemoglobin hematocrit, which, in this individual, clearly meets those criteria. There’s also the presence of a molecularly-defining lesion consisting with an MPN. So, theJAK2.

Next, this individual, by older criteria, clearly has polycythemia vera. Even by the new criteria, he clearly has that. Now the new criteria do also mandate the obtaining of bone marrow aspirate in biopsy. And I do think that that part is very helpful. It helps establish for me, do they have normal chromosomes or not? Do they have fibrosis as a starting place? So, if they are progressing, do we see that change? Do they have an increase in blast, or do they not?

It is controversial out in the community. Is that bone marrow really necessary for diagnosis? I’d say it’s at least helpful and certainly meets those criteria in a range of ways. If, for whatever reason, this individual did not have theJAK2mutation, then most certainly that bone marrow is incredibly helpful, as well as would be obtaining a serum erythropoietin level.

Individuals with very overt polycythemia vera frequently will have an inappropriately low serum erythropoietin level, whether that be normal or suppressed. It is also helpful as one has that EPO level in excluding that they do not have a secondary form of erythrocytosis. But the fact that this individual has theJAK2mutation, it makes a secondary form highly unlikely.

This individual started with therapy with phlebotomy and aspirin. When we think about treating patients with polycythemia vera, we know that control of the hematocrit is a key cornerstone. And that should be a hematocrit of 45% or less. We know now from randomized studies that achieving that goal is important. A randomized study compared polycythemia vera patients between a hematocrit of under 45% with 45% to 50%. And what they found is that even though the difference between those 2 arms sounds very subtle, the median of 1 arm was 48%, the median of the other was a hematocrit of 44%. There was a 4-fold difference in the rate of thrombotic events just between those 2 arms. It was highly relevant. I really use 45% as a clear ceiling.

Now, an individual like this who presented with headache and splenomegaly and hematocrit of almost 60%, I think is at acute risk of having an event, and it’s important to rapidly control their counts. An individual like that, I may do phlebotomy several times and relatively early with the course. Now, is that every 2 to 3 days? It depends a little bit on how well the patient tolerates the phlebotomy. I may use some fluid replacement. But when they are as extreme as this, I may use that fairly frequently and then down to weekly and then less until we at least try to get under 50% in terms of that most acute risk.

The second part of the treatment is aspirin. In the past, high-dose aspirin was found to be associated with an increased risk of bleeding ulcers. But subsequent modern studies, which tested a baby aspirin versus placebo, clearly showed the ability to decrease the rate of thrombotic events. So, both of those parts are clearly appropriate.

I think a discussion clearly could be held with the patient on the basis of symptoms, specifically on the basis of splenomegaly, and if they also should be considered for thrombotic events, for the use of a cytoreductive agent I should say more accurately. And I think that would be a discussion point with this individual. One might see, after the phlebotomy and aspirin, how much that helped to resolve either the symptoms or splenomegaly.

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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