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New Treatments for Polycythemia Vera

Polycythemia vera is usually suggested by a high hemoglobin or hematocrit. You have to make sure that the hemoglobin or the hematocrit that you are considering should be sex and race adjusted policythemia vera. The second thing which you have to realize is that all these indices, including hemoglobin, packed cell volume, hematocrit, red cell count, are all functions of ratios rather than actual red cell mass. For example, in a normal Caucasian male 50% hematocrit, 50% is plasma and 50% is red cells. If you go to an endemic area and get cholera you can very easily raise your hemoglobin to 19 and your hematocrit to 70 and that does not necessarily mean that you have PV. This is called relative polycythemia. On the other hand, you can actually have an increased red cell production but if you manage to grow a large spleen and expand your plasma volume, you can mask that and thus get a normal hematocrit and that is why this is called inapparent polycythemia.

So as you can see, these are not very sensitive and these minor criteria are very non-specific, and these criteria at this point are not used to diagnose PV. I never measure red cell mass in my patients. If you have a red cell mass baseline of, let’s say, 28 and you go up to 33 and you are a male then you have not fulfilled the criteria although you have had a biological increase in your red cell production. You have PV. On the other hand, if you did manage to increase it to 45 for one reason or another, you bled and when I measured your red cell mass and you are about 35, then you do not fulfill the criteria. These are some of the problems with measuring the red cell mass.

More importantly than the red cell mass, I think what you have to worry about is the presence of any clinical features that may be consistent with PV; pruritus, post-mass pruritus, erythromyalgic reactions. Any kind of acral dysthesia, pain, erythema, any kind of acral phenomena. Any unusual thrombosis especially involving the large vessels of the abdomen. Any person who comes up with any of these should be considered as having a hyper-coagulable state and one of the hyper-coagulable states are secondary to myeloproliferative disorders, PV and ET. Fortunately polycythemia vera is different from the other causes of erythrocytosis pathogenetically.

Well, we might come to the rescue. This is what we have been doing over the last year, thanks to Dr. Spivak and his colleagues at Hopkins a few years ago. Came out and showed us that megakaryocytes and platelets in patients with PV, and perhaps also in AMM, have an underexpression of the thrombopoietin receptor that can be actually revealed by histochemical states. These are commercial antibodies so we went out and got them and did a bunch of this and we were able to confirm that this was really true. This is normal megakaryocytes and, take my word for it, if you take an ITP patient who is reactive to megakaryopoiesis, which we have done, it’s the same thing. Bright expression of the thrombopoietin receptor and if you do it in a patient with PV it’s empty. Not only is it empty but it also brings out the abnormal megakaryopoiesis in that disease. So a bone marrow biopsy with histochemical stains are now complementary to morphological diagnosis in PV. Now we can do it. If you have patients you can send it to us. I think this is going to be a better and more reproducible.

How about cytogenetics? Forget everything here except this; only 17% of patients with PV will have cytogenetic abnormalities at diagnosis. Therefore it does not help you very much in distinguishing PV from reactive erythrocytosis. The good old days of diagnosing patients when they are so red in the face, or they have conjunctival effusions, or they have distended sausage-like retinal vessels, are gone. You will be lucky if one out of 20 of the patients that you see with PV have these marked clinical features.

Now you make the diagnosis of PV. What do you tell the patient? Well, before phlebotomy was instituted as treatment patients with PV died within two years. The reason why they died is because they thrombosed. Now the average survival in PV exceeds very easily 10-15 years. Why? Because phlebotomy was instituted and has been practiced for the last 80 years. The mainstay of therapy for PV is phlebotomy and when you phlebotomize them you have to phlebotomize them to a hematocrit of 45 for male and 42 for women and the corresponding figures for non-Caucasians. As you can see, the first ten years, as long as you phlebotomize

However, there is a growing concern about the possibility of leukemia being associated with a long term of hydroxyurea use. Although hydroxyurea is not a genotoxic agent, it is an agent nevertheless which impairs DNA synthesis and also DNA repair. So there is a legitimate concern regarding its potential leukemogenicity. Therefore, the next best thing to do is see if we can select the patients who have a high incidence of thrombosis and see if we can reserve treatment with additional hydroxyurea to those groups. That was done and it was possible. This risk stratification holds for both PV and ET so you don’t have to learn two risk stratifications for ET and PV. There’s only one. Low risk means that you are young - below age 60 - ( and when I am 65 it will be below age 70), you don’t have a previous history of thrombosis, you don’t have flagrant cardiovascular risk factors - obese, smoking, family history, what have you - and

Now that would be too easy, wouldn’t it? Because I know you are going to ask me, what about aspirin? What about the potential leukemogenicity of hydroxyurea? So before you keep me here to ask me those questions, I think I’ll just answer them now. Aspirin; if you use high dose defined as over 500 mg a day it’s bad. It causes gastrointestinal bleeding. So don’t use high dose aspirin. If you use low dose defined as 40-325 mg per day - I usually only use the baby aspirin which is only about 81 mg per day - then it is safe, it is safer. It appears that it probably does not cause as much gastrointestinal bleeding as a higher dose. Everybody knows that aspirin

Well, what about interferon? Well if I don’t say that interferon is the treatment of choice for young patients with PV. There is no question that it can control erythrocytosis and thrombocytosis. It can shrink the spleen and it is probably not too inferior to hydroxyurea. Also it is interesting that if you have a patient with refractory pruritus that interferon may do a better job of controlling that than hydroxyurea. However, I don’t know how your practice is, but interferon is a bad drug. It really reduces quality of life. And patients think that you are doing

Now the patients, some patients are going to be angry with you. They say, "Look, I’ve got PV. I’m not depressed." But you tell them, "Oh, PV causes its problems through serotonin-like agents" and then they agree to take the medication. It really helps. Have any one of you used Paxil for these patients? If you have a high risk woman of child-bearing age, meaning that the lady has a history of thrombosis, you have to treat the patient. But if they are of child-bearing

Now what about anagrelide? Well anagrelide is also now approved for polycythemia vera as you know. It’s a very effective drug to reduce platelet count. Here are the facts about PV and thrombosis. First of all, the degree of thrombocytosis has never been correlated with the risk of thrombosis in PV. Number two; the only thing which has been correlated with reduced thrombosis in PV is the use of pan-myelosuppressive agents, not a specific agent such as anagrelide. Therefore you really need to do a randomized study in order to see whether

If you look at patients with polycythemia vera treated with hydroxyurea only you can find incidence rates anywhere between 1-10%. Now therein also lies the incidence of risks of acute leukemia without any therapy too. So it’s very difficult to implicate hydroxyurea as a leukemogenic agent when you have such a discrepancy, and the risk is about 5% without any treatment anyway. When the Europeans randomized hydroxyurea against pepobromide, which for 20 years they said was not leukemogenic, there was absolutely no difference. But at this

The only thing I want you to look at on this slide is this and this. About 10% of patients with PV after ten years will develop myelofibrosis. It doesn’t appear that treatment changes this risk. The French will have you say something else, but in general I don’t think treatment influences this