Nazha Navigates Emerging Approaches for Polycythemia Vera Post Hydroxyurea

Aziz Nazha, MD, discusses risk stratification in polycythemia vera, options that have emerged for patients, approaches to consider following hydroxyurea, and the need for agents that will reverse fibrosis in the bone marrow.

Risk must be used to determine whether hydroxyurea (Hydrea) phlebotomy is the optimal first-line approach for patients with polycythemia vera, according to Aziz Nazha, MD, who added that alternative therapies such as ruxolitinib (Jakafi) and ropeginterferon alfa-2b (P1101) have emerged for those in whom the standard of care has failed.

For patients with lower risk, a phlebotomy can be done in an attempt to achieve a hematocrit level of less than 45%, said Nazha. For patients with higher risk, however, hydroxyurea is often used. For some patients, phlebotomy can be done in addition to hydroxyurea to control the hematocrit level. However, a subset of patients who receive hydroxyurea will experience drug failure. For this subgroup, ruxolitinib can be utilized, according to Nazha.

“Longer follow-up of the RESPONSE trial that led to the approval of ruxolitinib in polycythemia vera showed that almost 80% of those patients are still on the drug about 5 years later,” said Nazha. For those who progress on hydroxyurea and ruxolitinib, ropeginterferon alfa-2b has emerged as a potential option.

In June 2020, the FDA accepted a biologics license application for ropeginterferon alfa-2b for use as a treatment for patients with polycythemia vera in the absence of symptomatic splenomegaly. The application was based on data from the phase 3 PROUD/CONTI-PV clinical trial, in which patients with polycythemia vera were treated with either ropeginterferon alfa-2b or hydroxyurea/best available therapy. Results showed that the complete hematological response rate was much higher in the ropeginterferon alfa-2b arm compared with the control arm, at 70.5% versus 51.4%, respectively.

“We will reserve [ropeginterferon alfa-2b for] patients who are younger and in whom ruxolitinib [wasn’t really effective]. You can use it after hydroxyurea,” explained Nazha. “Some investigators also recommend using [ropeginterferon alfa-2b] up front, especially in patients who are younger. However, in older adults, we still can use this drug. There are adverse effects (AEs) but they’re very manageable.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Hematologic Malignancies, Nazha, a hematologist/oncologist at the Cleveland Clinic, further discussed risk stratification in polycythemia vera, options that have emerged for patients, approaches to consider following hydroxyurea, and the need for agents that will reverse fibrosis in the bone marrow.

OncLive®: How do you approach patients with polycythemia vera from the time of diagnosis?

Nazha: In terms of the diagnosis, data from the World Health Organization (WHO) established criteria to diagnose the disease; there are major and minor criteria. In the new revision of the WHO 2016 criteria, they recommended that a bone marrow biopsy be done in all patients as part of the evaluation of the disease. However, [there is] a small line [in the criteria] saying that in patients, especially males, if their hemoglobin is above 18.5 g/dL and [above] 16.5 g/dL for females, and they have a JAK2 mutation, you may consider not doing the bone marrow biopsy.

What are your thoughts on performing the bone marrow biopsy?

I personally highly recommend doing the bone marrow biopsy, for many reasons. Number 1, we want to ensure that the diagnosis actually is polycythemia vera because other myeloid neoplasms, such as myelodysplastic syndromes [and other] overlap syndromes, initially present like this disease or essential thrombocythemia. Then, when they progress, they show the full picture of the disease. It’s also important to quantify the amount of fibrosis in the bone marrow, because an increased amount of fibrosis at diagnosis could actually predict higher risk of the development of primary myelofibrosis in the future.

How do you approach risk stratification for patients once a diagnosis is established?

[Risk stratification involves] staging and it's very important because that is what guides our therapy. Risk stratification tools for polycythemia vera are the easiest [to use]. [Those classified as] higher risk, are patients who are above the age of 60 and/or have a history of thrombosis, [a history of] strokes, or any kind of vascular events; [they also have] clots in the veins, so in the legs, the abdomen, and so forth. Any patient under 60 years or who never experienced any thrombotic events, we consider to be lower risk. Our therapeutic decisions are then tailored based on that risk.

How is risk being used to inform treatment decisions in your own practice?

Everybody with polycythemia vera, regardless of the risk, should take baby aspirin. That's based on the ECLAP study, which randomized patients to receive baby aspirin or placebo; [results showed] that [those who take baby aspirin experience] a reduction of cardiovascular events, as well as thrombotic events.If the patient is at a higher risk for cardiovascular events, such as hypertension, diabetes, and heart problems, that [approach] should be optimized.

For patients with lower risk, the goal is to do phlebotomy and try to achieve a hematocrit level of less than 45%. The goal is to decrease the amount of fatalism [that we see]; by [achieving that level], we can decrease the thromboembolic events that happen in the disease compared with if we keep [the level] above 50%. We can achieve that with phlebotomy, which just takes blood from those patients at specific, frequent times; this can be tailored to the patient. Or, we can [achieve the desired level] by using cytoreductive therapy, such as hydroxyurea.

How do we choose [which approach to go with]? We start with a phlebotomy in any patient with lower risk. For patients with higher risk, we start with hydroxyurea. We [can also] add phlebotomy to the hydroxyurea to control the hematocrit [level].

Could you expand on some of the complications that can arise with this disease? How do you discuss this with your patients?

When I counsel patients, I tell them [if you compare a] patient with polycythemia vera to the general population, their survival is a little bit lower. But how [does] this disease affect the patient? Generally speaking, this is a chronic condition, which means that the patient is going to live with this disease. The first risk, as we discussed, is the risk of thrombosis or cardiovascular events, such as blood clots and stroke. If we can decrease that risk, we control the [blood] counts, [keep] the hematocrit [level] to 45%, then patients typically live an almost-normal life. The second risk for these patients is [that their disease will] progress to myelofibrosis. Typically, that happens [anywhere from] 7 to 15 years after diagnosis. Depending on the study that you look at, 15% to 20% of patients with polycythemia vera will progress to myelofibrosis.

This is an important point [to make to] my patients; I want them to understand the symptoms of when the disease progresses to myelofibrosis. Generally speaking, with polycythemia vera, the problem is actually having too many red blood cells. When the patient experiences anemia [we know] that could be an AE from therapy, but it also could be a sign that the disease [may] progress to myelofibrosis. Other signs include elevated lactate dehydrogenase. Other signs [can be found] in the peripheral blood; for example, polychromasia.

I also tell my patients that, generally speaking, about 50% of patients with polycythemia vera at diagnosis will have small [spleen], typically less than 5 cm. You can feel the tip of it but when that spleen [grows] 20 to 30 centimeters, that's not polycythemia vera; that's a sign of progression of the disease to myelofibrosis. Also, when we do a bone marrow biopsy, we like to see more fibrosis inside the bone marrow. I counsel patients on this because I want them to be aware. If they notice that their spleen is getting bigger, or if their labs were abnormal, that could be a sign of progression.

The last risk for those patients is that of progression to acute myeloid leukemia (AML); however, that risk relatively is low. Again, depending on the study that you look at, about 5% to 10% [of patients will progress to AML] and that could take a long period of time. From my experience, this risk is not something we can do anything about; it's part of the biology of the disease. I always mention that to my patients because everyone goes on Google and starts searching things. Then, [they ask whether] polycythemia vera is leukemia or whether there is any risk for leukemia. I always let them know that that risk is very low, but if it happens in the future, they are already prepared for that.

Could you speak to the goal of treatment? What should be done for patients who progress on hydroxyurea?

The standard of care is hydroxyurea for polycythemia vera with the goal to control the hematocrit to 45%. Now, we have a subset of patients with polycythemia vera in whom hydroxyurea has failed. In other words, you are unable to control the hematocrit to less than 45%; the spleen gets much larger despite treatment; or you put them on a high dose of hydroxyurea and then all their counts drop, so they cannot tolerate it. Others may experience AEs from hydroxyurea, such as bleeding, ulcers, or gastrointestinal toxicities.

Typically, the maximum dose that I recommend for patients with polycythemia vera is about 2 grams of hydroxyurea per day over 3 months. I wouldn't recommend [giving a] higher [dose of] hydroxyurea because typically what happens is that the other counts will start to drop. Let's say that you have a patient in whom you maxed out on hydroxyurea; they either cannot take it or they already [received] the [maximum] dose and their hematocrit never dropped below 45%. [Maybe you even] added phlebotomy [to the hydroxyurea] or you started playing what I call the “hydroxyurea game,” where you increased or decreased the dose, the counts rose or dropped, but you never find the sweet spot you were looking for.

[When that happens], there's the FDA-approved drug ruxolitinib. It should be noted that the approved dose for polycythemia vera is 10 mg twice daily. The same drug is also approved for primary myelofibrosis, [but in those patients you can give] about 20 to 25 mg twice daily. This is very important because I've seen some physicians start at 20 mg for polycythemia vera. Of course, you start the medication, but then you need to monitor the counts. The major AEs of the drug can be lightheadedness, headache, as well as the dropping of other counts, especially the platelets. This is why you have to monitor [patients] closely. In about one-quarter of the patients, you will have to adjust the dose, whether you're going to use 10 mg daily or 5 mg twice a day. A small subset of patients actually has to increase their dose, maybe 15 mg twice daily to be able to achieve hematocrit less than 45%.

We have other therapies that we can use [upon] hydroxyurea failure, such as interferon and pegylated interferon alfa-2a; we typically reserved that for younger patients. Interferon comes with AEs we need to manage very well. There are some other drugs that we can use off-the-shelf in case, for some reason, ruxolitinib stopped working or is not working anymore.

In June 2020, the FDA accepted a BLA for ropeginterferon alfa-2b. Should that agent receive approval, what impact could it have on the treatment paradigm?

I think it's a great drug. However, we have to be selective [of this drug] for our patients.

What challenges remain in the treatment of patients with polycythemia vera? Where do you think future research efforts should be focused?

The population of patients in whom ruxolitinib stops working need something else. As such, interferon or other investigational therapies will be good. If we're somehow able to find a drug or mechanism that prevents patients from progressing to myelofibrosis or AML, that will be of great interest.

Some small reports have shown that ruxolitinib can reverse a little bit of fibrosis in the bone marrow; however, we don't really have a good drug that is able to do that. The development of a drug that could somehow reverse fibrosis in the bone marrow may actually yield some interesting results in the future because maybe it will help to decrease the risk of progression to myelofibrosis.


US FDA accepts PharmaEssentia’s application for ropeginterferon alfa-2b to treat polythycemia vera. Published June 4, 2020. Accessed October 15, 2020.