Texas MPN Workshop 2021 | The current treatment landscape for polycythemia vera
Jerry Spivak, MD, Johns Hopkins University School of Medicine, Baltimore, MD, gives an overview of the current treatment landscape for polycythemia vera, highlighting the key treatment strategies used such as phlebotomy and chemotherapy. Prof. Spivak shares his thoughts on the use of phlebotomy to maintain a reduced thrombotic risk and how the use of hepcidin mimetics to negatively regulate iron metabolism may reduce the requirement of continuous phlebotomies, but may not necessarily address the issue of hyperviscosity. Additionally, Prof. Spivak addresses issues with phlebotomy-based strategies and describes how these can potentially be overcome with tyrosine kinase inhibitors or recombinant pegylated interferon. This interview took place at the Texas MPN Workshop: Second Annual Workshop and Meeting in 2021.
Transcript (edited for clarity)
The current treatment landscape for polycythemia vera is somewhat complex, and the reason for that is that there has been, for over 70 years, a heated debate as to the best treatment for this disease. And there are those like William Dameshek who felt that phlebotomy was the principal treatment. And those like the polycythemia vera study group who thought chemotherapy was better than phlebotomy...
The current treatment landscape for polycythemia vera is somewhat complex, and the reason for that is that there has been, for over 70 years, a heated debate as to the best treatment for this disease. And there are those like William Dameshek who felt that phlebotomy was the principal treatment. And those like the polycythemia vera study group who thought chemotherapy was better than phlebotomy. As it turns out, when polycythemia vera patients are first diagnosed, they have probably between 600 and 1500 ml of blood, excess blood in their vascular system. And since the major morbidity in this chronic illness is thrombosis, both arterial and venous, the first treatment need is to reduce blood viscosity and also remove nitric oxide scavenging by red blood cells. And as soon as that is done, I believe we’ve lowered the thrombotic risk to that of the general population. And that can be maintained by periodic phlebotomies to a sex-specific hematocrit.
There is a trend in the literature to forget that women with polycythemia vera are not small men. They have smaller blood volumes because they don’t manufacture the same amount of androgens as men do. Now, there is on the horizon, some interesting experimental work using hepcidin and analogs to block iron absorption in polycythemia vera. And this is a way possibly to get around maintenance phlebotomy, but it can’t, as far as I can see change the hyperviscosity situation when patients are diagnosed.
Now, the other side of the coin here is that in polycythemia vera, plasma volume is expanded. So, the rules for hematocrit targets go out the window until you have a reduced blood viscosity. And then you keep men under 45% hematocrit and women under 42% or even lower. And this was a big mistake. If you don’t adhere to this, particularly in patients who have hepatic vein thrombosis, usually women, who may need to be phlebotomised down as low as 35%. And this is true in pregnant women.
Now, thereafter, the question is, well, what about the high platelet count? Or what about the high leukocyte count? Well, a recent study importantly showed that leukocytes are not responsible for thrombosis in polycythemia vera and platelets are not responsible for thrombosis in polycythemia vera. The platelets may be sticky and patients with good ocular migraine or erythromelalgia, and there aspirin, usually Asp inhibitors other than Asp or aspirin, tend to be very effective with phlebotomy. With respect to the leukocytes, unless patients have hyperuricemia or unless white count is going over 30,000 and there is increasing splenomegaly, there’s no need for phlebotomy because these cells do not promote thrombosis. The other issue that phlebotomy cannot correct is splenomegaly. And this is, I want to emphasize that only a small fraction of patients, some 15 or less than 15% of polycythemia vera patients are going to get big spleens.
And I think here there are two ways to treat the patient. One is to use a tyrosine kinase inhibitor, such as ruxolitinib or for fedratinib. And the other is to use a recombinant pegylated interferon. The former only kills off the dividing cells. And so will normalize blood counts and shrink spleens, but not in everybody. In the latter, the interferon targets the hematopoietic stem cell that’s involved in polycythemia vera. And you can actually produce remissions in many people, or there’s an effect called the CML effect. Patients with CML who were given interferon before they received imatinib went into remission faster and more durable remissions when they were treated with interferon before imatinib. And I, to say this is only a clinical feeling from patients that I treat that even if you don’t get a complete remission, having seen interferon, patients tend to have less aggressive disease. But what’s an unmet need here are the group of patients who need interferon but don’t get the benefit of the drug for reasons that we don’t understand. And it may be when to start interferon?
As for chemotherapy, I look at that as sort of an emergency use to lower blood counts when they need to be lowered quickly, perhaps for surgery or for symptomatic reasons when interferon does not work. But there’s no question that we need newer treatments in polycythemia vera that do not involve chemotherapy and are more efficacious than recombinant interferon.
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