Harry P. Erba, MD, PhD: We have these therapies. We have hydroxyurea, phlebotomy, aspirin, and interferon in selected patients. How do we then describe, understand, or recognize the patient who has progression of their disease and needs something beyond those agents? Srdan, do you want to handle that?

Srdan Verstovsek, MD, PhD: We all agree that the goal of therapy is at the level of 5 factors. We have control of red blood cells, white cells, platelets, symptoms, and spleen. This is what we want to achieve. It’s intuitive then to say progression or loss of control—maybe that’s better in some cases—is progress with splenomegaly or symptomatic splenomegaly; symptomatic thrombocytosis; progressive leukocytosis; and need for phlebotomies, which may be frequent and perhaps even symptomatic to a patient. Not eliminating frequent phlebotomies would be 1 failure of the therapy. White count control, red blood cells, platelets, symptoms, spleen, and platelets. We already talked about symptoms. Even with control of the blood cell count, you can have a very symptomatic patient; you need to talk about the person, not about the numbers.

I agree that 45% hematocrit control is proven in prospective randomized studies to be key, but everything else is important, as well—particularly, quality of life for the patient. So, if you don’t have these 5 factors covered very well, you may actually think about changing the therapy. Then you have intolerance to therapy. Ruben has described intolerance to hydroxyurea very well. Obviously, you would change therapy. The last issue is an actual event, thromboembolic event or hemorrhagic event, while you are controlling all the factors with, let’s say, hydroxyurea. If a patient is on hydroxyurea, the numbers are good, and quality of life is OK, but the patient has pulmonary emboli or has MI, I would probably consider that a failure, because what you’re trying to do is, with the control of the count, eliminate or decrease the risk of thromboembolism. If you have it, you probably would consider changing to the next line of therapy. It depends on the degree of difficulty and what kind of event you are talking about. But that’s No. 7. You have these 5 factors plus intolerance, No. 6, and 7 is actually when to consider changing therapy from frontline to second line.

Harry P. Erba, MD, PhD: I have trouble with that one, and I want to bring that up for discussion. A new thrombotic event occurs, but the patient has no constitutional symptoms, no splenomegaly, and all of their blood counts are well controlled. What data do we have that changing from hydroxyurea to interferon or from hydroxyurea to ruxolitinib or our available agents can actually negate or reduce that risk even further? Let’s not forget it depends on the event. If it’s Budd-Chiari syndrome, maybe. If it’s an MI in somebody with hypercholesterolemia, I’m not so certain.

Rami Komrokji, MD: Yes, I think it’s the clinical setting.

Harry P. Erba, MD, PhD: The clinical setting, right.

Rami Komrokji, MD: If you have a good alternative explanation. If you have uncontrolled counts in that setting and you don’t have a good explanation as to why somebody has an acute MI out of the blue or a DVT that’s not explained, I think that could justify changing the treatment. You are right, we don’t have solid data for that, but I think that’s where your clinical sense weighs in on those things.

Jamile M. Shammo, MD, FASCP, FACP: I think that’s a very important point. To me, if someone has an MI and they have coronary artery disease, my question is if I have done them a disservice by not controlling their counts. I like to look at the CBC at the time of the event, because in a way, this is what was done in the Marchioli data. They looked at the CBC immediately preceding the thrombotic event. If there was an abnormality there, then this obviously may have been related to uncontrolled counts. It’s as if it’s a failure of a therapeutic INR because it fluctuates over. I tend to think that perfect control of counts is truly the mainstay of therapy in this case.

Ruben A. Mesa, MD, FACP: I’d say the most common scenario, when you really dig into the points that Jamile raises, is that they’re really not well controlled when the event occurs. Fundamentally, it’s usually because of the issue of tolerance. I have a lot of patients who come to see me who are controlled on hydroxyurea because they’re on their maximum tolerated dose. But even with that, they’re needing phlebotomies, their white count is high, and their platelets are high. So, they’re not well controlled at all, but they’re on hydroxyurea. It just is not tolerated, so it really is ineffectual. The event is usually in that time. To really raise the individuals, we really need to change course to achieve that protective level of control.

Harry P. Erba, MD, PhD: What I’ve heard from you all is that a new thrombotic event in a patient should be a red flag that maybe the disease isn’t controlled, and we should work to look at that, ameliorate those factors, and maybe change therapy if necessary. One thing I’d like to add to your discussion about progression is that this phlebotomy issue is not quite as benign as it’s been made out to be over the years. I think one of the biggest complications of it is iron deficiency. That is the whole goal of it. Iron deficiency can really affect the quality of life of our patients. I think we need to keep that in mind when talking about how we’ll just use phlebotomy month after month.

Transcript Edited for Clarity