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Treating Leukocytosis in Polycythemia Vera

Panelists: Harry P. Erba, MD, PhD, Duke University; Rami Komrokji, MD, Moffitt Cancer Center; Mary Frances McMullin, MD, FRCP, FRCPath, Queen's University Belfast; Ruben A. Mesa, MD, FACP, UT Health San Antonio MD Anderson Cancer Center; Jamile M. Shammo, MD, FASCP, FACP, Rush University Medical Center
Published: Tuesday, Jul 23, 2019



Transcript:

Harry P. Erba, MD, PhD: I agree with all of those. You’ve left a few out that are sometimes mentioned—splenomegaly, and not just splenomegaly, but symptomatic splenomegaly. We often feel a spleen tip. It doesn’t mean we have to start therapy, but the one that I find the most controversial among my colleagues is leukocytosis.

Ruben A. Mesa, MD, FACP: True. It’s an excellent point. I think if we look at our goals of therapy by our current European LeukemiaNet criteria, it helps us to back up a little bit into some of these parts. Leukocytosis, through many different analyses, and now even a more recent meta-analysis, clearly is a risk factor for thrombosis. Now, there are a couple caveats. One, we don’t have definitive proof that the correction of leukocytosis gets rid of that risk. We assume that, and I think it’s reasonable, given the overall relatively lower risk of the therapies that we’re utilizing for these individuals. Can I prove that correcting it decreases that to a lower degree? I would say that the symptom part is a key part, as it relates to the spleen or vascular symptoms from the counts being too high, or things of that nature.

The other point I would make that’s key is that it’s a very dynamic disease, meaning there’s your initial part, but then there’s the monitoring. Patients need to have their blood counts monitored, clearly more frequently at first, as they’re getting their phlebotomies to get their hematocrit under control. I’d say for patients who are more in a maintenance phase, in my clinic, every 6 to 8 weeks they get at least a blood test. They may not need a face-to-face visit at that frequency, depending upon how they’re doing, but I do think blood counts should not be too spread out, so that if you’re getting off the rails either in terms of progression, overshooting, etcetera….

Finally, really serial evaluation of the difficulties that they’re following is necessary. Pruritis and these other symptoms are really important to take into account. These are not patients who are solely managed on the basis of how well their counts are controlled.

Harry P. Erba, MD, PhD: In the CYTO-PV [Cytoreductive Therapy in Polycythemia Vera] study published by Roberto Marchioli MD, there was clearly a difference in the risk of thrombotic events—less than 45% or 45% to 50%. Even though the study never finished accrual, there was still a difference at 3 years. Then, Tiziano Barbui MD did a secondary analysis of that study showing that the risk of thrombosis was also linked to the white blood cell count by dividing patients into quartiles, and showing with each quartile, especially when you get over 11,000, that there’s a higher risk of thrombosis. Mary Frances, not that you speak for all of Europe, but is there a different perception in Europe in terms of the white blood cell count? Should it be treated?

Mary Frances McMullin, MD, FRCP, FRCPath: I think that’s a very difficult question. You come up with the 11. Some of the other studies talk about a 15 cutoff. If you say, “Control the white cell count,” what white cell count? Again, when we wrote our guidelines, we looked at all this and said you couldn’t actually come up with a level where you wanted to keep that white cell count below. I don’t think anyone in Europe will advocate treating solely on the basis of a white cell count. The patients we’re wary of are the patients whose white cell count is going progressively up, and that’s where you may want to come in, even in a low-risk patient, to consider cytoreductive therapy.

I think it’s very difficult. This question comes up all the time because of all those papers. This patient’s white cell count is 12, should I treat them? However, lots of patients have that. Smokers have high white cell counts and they sit at that. It’s the one that’s progressively going up that I would be wary of. I also say I certainly have many patients in my clinic with high white cell counts, and they get their cytoreductive therapy and they get their hematocrit controlled, but it’s actually very difficult to get the white cell count down.

Rami Komrokji, MD: I see it as one of the risk factors, for sure. Like Ruben was saying, you have to put all this information together to decide. It definitely could be information that’s helpful. The challenge, even from the study, is we don’t know if that hematocrit control was just from the phlebotomies or cytoreductive therapy. The patients on that study who had hematocrit less than 45% did better, but some of those patients did get cytoreductive therapy, and that also controlled their white count. It’s really challenging in patients who will just be getting phlebotomies where their hematocrit is controlled and they still have leukocytosis, to figure out the impact of the leukocytosis. It’s definitely, for me, one of the risk factors and something we monitor.

Off topic a little bit, we are starting to look at leukocytosis in other diseases like myelofibrosis and CMML [chronic myelomonocytic leukemia]. Historically, we were trained that you don’t do anything, you just observe them. Now, actually, if you start digging into it a little bit more, you do start to see some end organ damage like renal impairment, pleural effusions, and complications for patients who have leukocytosis. We will probably be revisiting the issue of leukocytosis, not just in PV, but in all those myeloproliferative diseases.

Harry P. Erba, MD, PhD: Even outside of neoplasms, if you go back to the data supporting the use of hydroxyurea in sickle cell, we hypothesized that hydroxyurea increased hemoglobin F levels, and gets metabolized to nitric oxide, a vasodilator. Remember, in those studies, the hydroxyurea and placebo doses were pushed to get the white counts lower. Could it be that the decreased risk of vaso-occlusive crises was actually related to the reduction in leukocytosis?

Transcript Edited for Clarity

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Transcript:

Harry P. Erba, MD, PhD: I agree with all of those. You’ve left a few out that are sometimes mentioned—splenomegaly, and not just splenomegaly, but symptomatic splenomegaly. We often feel a spleen tip. It doesn’t mean we have to start therapy, but the one that I find the most controversial among my colleagues is leukocytosis.

Ruben A. Mesa, MD, FACP: True. It’s an excellent point. I think if we look at our goals of therapy by our current European LeukemiaNet criteria, it helps us to back up a little bit into some of these parts. Leukocytosis, through many different analyses, and now even a more recent meta-analysis, clearly is a risk factor for thrombosis. Now, there are a couple caveats. One, we don’t have definitive proof that the correction of leukocytosis gets rid of that risk. We assume that, and I think it’s reasonable, given the overall relatively lower risk of the therapies that we’re utilizing for these individuals. Can I prove that correcting it decreases that to a lower degree? I would say that the symptom part is a key part, as it relates to the spleen or vascular symptoms from the counts being too high, or things of that nature.

The other point I would make that’s key is that it’s a very dynamic disease, meaning there’s your initial part, but then there’s the monitoring. Patients need to have their blood counts monitored, clearly more frequently at first, as they’re getting their phlebotomies to get their hematocrit under control. I’d say for patients who are more in a maintenance phase, in my clinic, every 6 to 8 weeks they get at least a blood test. They may not need a face-to-face visit at that frequency, depending upon how they’re doing, but I do think blood counts should not be too spread out, so that if you’re getting off the rails either in terms of progression, overshooting, etcetera….

Finally, really serial evaluation of the difficulties that they’re following is necessary. Pruritis and these other symptoms are really important to take into account. These are not patients who are solely managed on the basis of how well their counts are controlled.

Harry P. Erba, MD, PhD: In the CYTO-PV [Cytoreductive Therapy in Polycythemia Vera] study published by Roberto Marchioli MD, there was clearly a difference in the risk of thrombotic events—less than 45% or 45% to 50%. Even though the study never finished accrual, there was still a difference at 3 years. Then, Tiziano Barbui MD did a secondary analysis of that study showing that the risk of thrombosis was also linked to the white blood cell count by dividing patients into quartiles, and showing with each quartile, especially when you get over 11,000, that there’s a higher risk of thrombosis. Mary Frances, not that you speak for all of Europe, but is there a different perception in Europe in terms of the white blood cell count? Should it be treated?

Mary Frances McMullin, MD, FRCP, FRCPath: I think that’s a very difficult question. You come up with the 11. Some of the other studies talk about a 15 cutoff. If you say, “Control the white cell count,” what white cell count? Again, when we wrote our guidelines, we looked at all this and said you couldn’t actually come up with a level where you wanted to keep that white cell count below. I don’t think anyone in Europe will advocate treating solely on the basis of a white cell count. The patients we’re wary of are the patients whose white cell count is going progressively up, and that’s where you may want to come in, even in a low-risk patient, to consider cytoreductive therapy.

I think it’s very difficult. This question comes up all the time because of all those papers. This patient’s white cell count is 12, should I treat them? However, lots of patients have that. Smokers have high white cell counts and they sit at that. It’s the one that’s progressively going up that I would be wary of. I also say I certainly have many patients in my clinic with high white cell counts, and they get their cytoreductive therapy and they get their hematocrit controlled, but it’s actually very difficult to get the white cell count down.

Rami Komrokji, MD: I see it as one of the risk factors, for sure. Like Ruben was saying, you have to put all this information together to decide. It definitely could be information that’s helpful. The challenge, even from the study, is we don’t know if that hematocrit control was just from the phlebotomies or cytoreductive therapy. The patients on that study who had hematocrit less than 45% did better, but some of those patients did get cytoreductive therapy, and that also controlled their white count. It’s really challenging in patients who will just be getting phlebotomies where their hematocrit is controlled and they still have leukocytosis, to figure out the impact of the leukocytosis. It’s definitely, for me, one of the risk factors and something we monitor.

Off topic a little bit, we are starting to look at leukocytosis in other diseases like myelofibrosis and CMML [chronic myelomonocytic leukemia]. Historically, we were trained that you don’t do anything, you just observe them. Now, actually, if you start digging into it a little bit more, you do start to see some end organ damage like renal impairment, pleural effusions, and complications for patients who have leukocytosis. We will probably be revisiting the issue of leukocytosis, not just in PV, but in all those myeloproliferative diseases.

Harry P. Erba, MD, PhD: Even outside of neoplasms, if you go back to the data supporting the use of hydroxyurea in sickle cell, we hypothesized that hydroxyurea increased hemoglobin F levels, and gets metabolized to nitric oxide, a vasodilator. Remember, in those studies, the hydroxyurea and placebo doses were pushed to get the white counts lower. Could it be that the decreased risk of vaso-occlusive crises was actually related to the reduction in leukocytosis?

Transcript Edited for Clarity
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