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Dr. Prithviraj Bose:
Welcome to The ASCO Post Roundtable Series on Updates in Myeloproliferative Neoplasms. I am Prithvi Bose and I'm one of the associate professors in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. And joining me today is my colleague, Dr. Ruben Mesa.
Dr. Ruben Mesa:
Thank you Prithvi. I'm honored to be here. I'm the executive director of the Mays Cancer Center at UT Health, San Antonio MD Anderson and delighted for our discussion today.
Thank you, Ruben. Today, we will be discussing the role of strict hematocrit and white blood cell count control in managing the risk of thrombosis in a patient with polycythemia vera. Let's get to the case. So we have a 57-year-old male that comes to your clinic for frequent headaches and dizziness. He is a former smoker. A bone marrow biopsy is done and shows trilineage proliferation and pleomorphic megakaryocytes. NGS on the bone marrow shows the JAK2 V617F mutation at an allele burden of 65%. Presenting blood counts include a white blood cell count of 21,000/L, hemoglobin of 22 g/dL, hematocrit of 66%, platelets of 650,000/L and the MCV is 72 fL. The diagnosis of polycythemia vera is made. Aspirin 81 mg/d is initiated along with phlebotomy once monthly for a goal hematocrit of less than 45%. Ruben, initial thoughts on this presentation and the management plan.
Sure. So this is an individual who clearly presents with very significant proliferation. They have marked erythrocytosis and with that a hemoglobin of 22 g/dL. They present with a baseline leukocytosis which is always a bit of a concern for me in terms of risk, cardiovascular risk, and others. Although by the age criteria for risk, this individual is under age 60. I recognize that this is a continuous variable and the closer one is to 60, the greater the likelihood of both thrombotic and bleeding events. Indeed, I think the age factor is a bit of a reflection of older blood vessels, more cardiovascular risk, and other factors. So this is an individual I have the strong sense early on, may require more than just phlebotomy and aspirin due to their age, as well as how they have presented.
Ruben, would you phlebotomize them a little bit more often just looking at how impressive those numbers are? Or do you think the once monthly would suffice here? What are your views on that?
I think that in such an individual, I would probably do phlebotomies as tolerated to get them into a safer range. So if they had presented with an acute event, let's say they were hospitalized with a thrombotic event, I might try to do it really as tolerated every 3 or 4 days. Someone like this with a hemoglobin this high, I would probably do it at least weekly, assuming they were tolerating the phlebotomies okay. They may need in that early setting, some replacement of fluids, maybe even a little bit of albumin if symptomatic from the phlebotomies, but I don't think that you have several months to get them into a safe range. I think one can go probably 4 to 6 months by only phlebotomizing once a month for such an individual and that's a lot of cumulative risk to build up. I think one needs to be more aggressive.
Absolutely. Thanks Ruben. So now we fast forward to the 3 month follow up for this patient. Again, remember, the management plan was aspirin 81 mg/d, that's a baby aspirin and once monthly phlebotomy. And so at 3 months, the hemoglobin is 20 g/dL, hematocrit is 60%, the white count is 22 x 109/L, and the platelet count is 680 x 109/L. So all the numbers are pretty much the same or slightly higher, and he has continued headaches, dizziness, and nausea. At this point, hydroxyurea 1 g/d is added, and the phlebotomy is now moved up to every other day to a target hematocrit of less than 45%. Comments here, Ruben?
I think that the consideration of cytoreductive therapy can be made even earlier on in the course of this individual's course. So as I try to share with patients, what are the indications for cytoreduction? I think the strongest ones we have are age over 60 years and a prior thrombotic event. However, just below that, are (1) difficult symptoms that are not controlled with phlebotomy alone and (2) leukocytosis as a risk factor. Maybe in isolation may not be enough of an indication on its own, but when one combines that with the extreme erythrocytosis for this individual and almost being at age 60, I think one could anticipate that that's going to be necessary. One also has the thrombocytosis that this individual has. So all of these things really are contributing. Now as we look at this 3 month follow up, this individual has symptoms. The hydroxyurea I think probably would have been necessary or some sort of cytoreduction to really have any expectation of having count control for not only the red cells, but the white cells and the platelets.
I think as we had discussed, the having phlebotomy be just once a month, led to too slow of control of the hematocrit. That being said, I think changing to as frequent as every other day, probably the patient would not tolerate. So I think there's probably a middle ground in-between for more accelerated phlebotomy on the front end and then spacing it out, and then probably the initiation of cytoreduction. I do think the starting dose of hydroxyurea at 1,000 mg is certainly reasonable, but probably would've done it earlier on in the course of disease, and then really seeing how they were tolerating that approach.
Completely agree in this very proliferative patient. So, 3 months later, we have another follow up and at this point, the counts are better in terms of hemoglobin and hematocrit, but still above goal at 16.3 g/dL for the hemoglobin and 49% for the hematocrit. The white count is pretty much untouched despite the hydroxyurea, at 23 x 109/L now, and the platelets are a little bit lower at 590 x 109/L, from 680 x 109/L at the 3-month mark. Ferritin is 7 ng/mL , indicative of iron deficiency, obviously. And the erythropoietin remains suppressed at less than 3 mU/mL, essentially not detectable. The patient now has pruritus and the hydroxyurea at this point, at 6 months, is bumped up to 1,500 mg/d. How would you manage this at this point, Ruben?
This individual clearly is not doing well on the current approach. They have significant itching. They've gone up to an MTD of hydroxyurea at 1,500 mg/d, they're iron deficient, and are nowhere near where we want in terms of a European LeukemiaNet complete heme response. Our goals in P-Vera are to one, keep the hematocrit under 45% and unfortunately 6 months in, we have yet to achieve that. Second, if we're using cytoreduction to have a white cell count under 10,000/L and a platelet account of under 400,000L. Again, really not having success in that regard. Third, improvement in splenomegaly or symptoms if they are present. So this is an individual, I think, that is meeting the criteria for really an inadequate response to hydroxyurea. And in such an individual, maybe considering second-line therapy, such as ruxolitinib, which is FDA approved in this sort of situation, might be very beneficial for control of all three of the blood counts, but also have a favorable impact on the pruritus.
Additionally, by good control of the counts, there will be less of a need for phlebotomy, and then hopefully a correction over time of the iron deficiency. Indeed, this entire pattern would be suppressed ferritin all suggests a state of iron deficiency, which tends to really increase the symptom burden these patients can face. They can have fatigue, it can worsen the pruritus, it certainly can aggravate issues like restless leg syndrome and other difficulties that patients can face. So, I think for this individual, I probably would've used hydroxyurea earlier on in the course of disease, been more aggressive with my upfront phlebotomy strategy, and then transitioned to ruxolitinib as second-line therapy, if not achieving my goal or the patient was intolerant of hydroxyurea.
Certainly. Thanks Ruben. So just for our listeners, the European LeukemiaNet that Ruben alluded to, provides a nice framework for resistance or intolerance to hydroxyurea, which is really helpful to guide clinicians in the sense that it sort of lays out some of the situations in which one can be considered to be failing hydroxyurea. And without going through all of those, the general spirit of it is that either you are not controlling the myeloproliferation, despite the maximum tolerated dose for a reasonable period of time, or that you're causing side effects and cytopenias in trying to get that hematocrit down.
We'll move from there on to essentially our key clinical takeaways, hopefully from this case and this discussion. I'll start by saying that hematocrit of under 45% is always the goal. That's always the target. This is based on the CYTO-PV study and the goal here is obviously to reduce the risk of cardiovascular and thrombotic events. Less than half of patients will maintain this goal consistently, that is consistently maintain a hematocrit less than 45% if you use just phlebotomy.
Now, high risk patients, as Ruben alluded to earlier, patients who are over 60 years of age and, or have had a prior clot, should always receive cytoreductive therapy. The phlebotomy-only approach is really more applicable to low-risk patients. However, even among low-risk patients, there are potential indications as Dr. Mesa alluded to, for cytoreductive therapy. And these are, if there is a new thrombosis or disease-related major bleeding, if they're requiring too frequent phlebotomies or are intolerant of them. Again, there's not a definition of what is too frequent, but this is something that has to be individualized.
If they have progressive splenomegaly, progressive leukocytosis, because of the association with clotting and other adverse outcomes, such as leukemic transformation and inferior survival, as well as symptomatic thrombocytosis, stuff like migraines and other microvascular complications, or disease-related symptoms like this patient was having, pruritus, night sweats, fatigue, and others, that are not adequately controlled by hydroxyurea.
Finally, in terms of evidence on the leukocytosis piece of this, the ECLAP study, a sub-analysis of the CYTO-PV study, and the more recent REVEAL study, all showed that an elevated white blood cell count, perhaps the best cutoff there is 11 x 109/L, so above 11 x 109/L is associated with an increased risk of thrombosis. This actually brings us to the end of this case. Thank you, Ruben, so much for all your insights. And for our listeners, please see the other segments for further discussion about the latest data in MPNs or visit ascopost.com.