PV Progression and Guideline-Directed Management

Ruben A. Mesa, MD: Following a patient with polycythemia vera [PV], we dually are trying to be sure that we’re preventing thrombosis and bleeding, controlling symptoms, but we always have an eye on the issues of disease progression. Polycythemia vera can progress in 1 of 2 ways. One, it can progress into myelofibrosis. That progression typically is accompanied by enlargement of the spleen. It’s accompanied typically by a change in the symptom profile, the development of fatigue, that is different from what had existed before. Spleen-related symptoms, catabolic symptoms, such as inadvertent weight loss. Indeed, in our society nobody—yours truly included—loses weight without trying. Sometimes even when you try, you don’t lose weight. When a patient comes in and he tells me they’ve lost 20 pounds and didn’t try, sadly I know that means something has changed profoundly in terms of their metabolism to have that happen. That too can be a strong indicator that something has taken a change for them.

Additionally, there is a change in the profile of the counts where one begins with erythrocytosis. Perhaps they become iron deficient and have still a robust hemoglobin, but over time they might develop anemia, even if the iron deficiency has been corrected. That’s a major red flag of the disease changing.

There can tend to be a progressive leukocytosis. There can be leukoerythroblastosis, where we begin to see changes in the differential, myelocytes, metamyelocytes, other earlier myeloid cells being released in the circulation earlier than normal because of the fibrosis process occurring in the bone marrow. Additionally, there can be enlargement of the spleen sometimes to a significant degree.

We then confirm that there has been a change with repeating the bone marrow aspirate and biopsy showing a change with increase in reticulin fibrosis, rarely increases in collagen fibrosis, not uncommonly, the development of additional karyotypic abnormalities or other NGS [next-generation sequencing] mutations that can arise for these individuals.

The NCCN [National Comprehensive Cancer Network] Guidelines are helpful for the management of MPNs [myeloproliferative neoplasms], and I’m honored that Dr [Srdan] Verstovsek and I were involved with the inaugural development of these guidelines. Guidelines help to provide the guardrails of therapy. What should we be considering and what are decision points? In a patient with P [polycythemia] vera who is already on management—whether that’s with a current cytoreductive therapy or they’ve not begun cytoreductive therapy—if they have a thrombotic event, that clearly is something we are trying to avoid. We must circle back and say should that trigger a change in therapy. If they were not on cytoreductive therapy, it likely means that we should begin cytoreductive therapy. If they were on cytoreductive therapy, it raises the question if it has failed. I look to see if the counts were adequately controlled. Was the therapy achieving what we needed to. Was that patient being compliant in terms of the therapy? If the goal was to have their counts controlled with Hydrea but they weren’t taking it, then they haven’t necessarily failed Hydrea. If we can get them back on Hydrea, great, but if they were on fully therapeutic Hydrea and the counts were controlled and they still had an event, that would certainly trigger the thought of thinking of them as being hydroxyurea resistant, and we might switch them to ruxolitinib or an alternative second-line therapy.

Indeed, it is key whenever we’re employing 1 of these approaches, and we decide whether they’ve been beneficial or whether we need to change gears. What is the target? Let’s say that with hydroxyurea, the target is to get the platelet count under 400,000 per mm3, the white count under 10 per mm3, the hematocrit under 45% without needed phlebotomy. Are they able to achieve that in a way that is tolerated? You give them the medication, but it takes a dose that leads to excess of toxicity. That’s another reason for failing hydroxyurea. If with the dose that they’re on they’re not achieving that, we need to push the dose to achieve that goal. Either we achieve that goal or we decide they’re not tolerating the medicine sufficiently, they’re resistant, then we’ll consider switching. That is crucial both for the NCCN Guidelines as well as the European LeukemiaNet guidelines: Are they having benefit or are they not?

If not, if they fail hydroxyurea, then we have indicated ruxolitinib, the JAK inhibitor, that both can help in terms of that thrombosis and phlebotomy-free survival for the patient with PV. But that also can be beneficial in terms of evidence of progression with either splenomegaly, difficult symptom control and those challenges in terms of progression.

Transcript edited for clarity.