Prithviraj Bose, MD

As far as future directions and unmet needs, and potential for drug development in PV [polycythemia vera], the need to modify the risk of myelofibrosis and AML [acute myeloid leukemia] is probably the No. 1 unmet need that we need to investigate new therapies for. As far as new drugs in the field, there’s a drug called rusfertide, which is a hepcidin mimetic. This is a drug with a narrow but specific role, which is to reduce the need for phlebotomy. By mimicking the action of hepcidin, it can make sure that the iron is less available for erythropoiesis and is sequestered in the reticular endothelial system.

There is a limitation in terms of the iron that’s available for erythropoiesis. In this way it’s able to reduce or eliminate the need for phlebotomy and correct iron deficiency. That’s a novel mechanism and a drug that does what it’s designed to do. This is something on the horizon, but its role is well defined. It would be used to reduce the need for phlebotomy, rather than a more holistic approach to the disease in terms of reducing clots, ameliorating symptoms, reducing spleen size, and controlling blood counts, which are achieved by ruxolitinib [Jakafi]. Of course, reducing the need for phlebotomy and controlling the hematocrit remains a central goal in PV, and rusfertide is an exciting drug in that sense.

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Description: Before closing out his discussion on polycythemia vera management, Prithviraj Bose, MD, shares excitement for emerging therapeutics in this setting.

Unmet Needs and Future Directions in Polycythemia Vera Management

Coming back to our patient, to make a data-driven, evidence-based recommendation, I’d treat this patient with ruxolitinib [Jakafi]. That’s what I go to in situations of hydroxyurea resistance and intolerance. Clearly this is a high-risk patient with proliferative disease, needing phlebotomies a lot, symptoms, a big spleen—all things that are amenable to being nicely controlled by ruxolitinib. That’s where the data are as well. As I said, after 5 years, we have no new safety concerns and sustained efficacy. To me, it would be a no-brainer to go with ruxolitinib in this setting.

There are discussions regarding disease modification and the long-term risks of myelofibrosis and acute myeloid leukemia, which unfortunately are real even though they’re quite small. The risks at 10 and 15 years are relatively low, but they’re there. To give you some ballpark numbers, at 10 years, there’s a 4.9% to 6% chance of developing post–PV [polycythemia vera] myelofibrosis and a 2.3% to 14% chance of developing AML [acute myeloid leukemia]. At 15 years, these go up a little to 6% to 14% chance of developing post PV myelofibrosis and a 5.5% to 18% chance of developing AML. These are numbers I’m quoting from 1 study, but this study looked at the literature as a whole and tried to summarize the incidence.

These are problems, and we don’t have good evidence that any of our therapies modify this risk, unfortunately. We don’t know that. It has been said that interferons may have a role. That remains to be proven, but they do lower the JAK2 allele burden. That might be extrapolated into as a measure of disease modification. But this hasn’t been shown to clearly translate into clinical outcomes. However, some data from certain groups suggest that pegylated interferon regimens may be able to retard the progression to myelofibrosis. It’s far from settled, and this is something that needs further investigation.

The reduction of the JAK2 allele burden is clearly a strength of interferons, but this is also seen with ruxolitinib. In the RESPONSE trial, over time there was a clear reduction in JAK2 allele burden, and that ended up being about a 50% reduction in a good number of patients, with the mean reduction of the allele burden being around 40% in the long term follow-up, which was up to 4 years at the time this was reported.

In terms of what to tell patients with regard to MF [myelofibrosis] and AML [acute myeloid leukemia] risks, as well as overall goals and thrombosis reduction, we don’t have proven interventions to change the risk of myelofibrosis and AML. The ropeginterferon alpha-2b is recently approved, and interferons may not have the potential to do this. That remains to be seen. However, in terms of long-term disease control, in terms of controlling the blood counts, symptoms, the spleen—things we know are important in terms of quality of life and clotting risk—ruxolitinib has the most robust data in the second-line setting after hydroxyurea failure to achieve those end points.

We didn’t talk about clot reduction with ruxolitinib, but that was shown as well. It wasn’t an efficacy end point in the RESPONSE trials. Thrombosis reduction wasn’t 1 of the end points the trials were powered for, but they were definitely looked at as safety end points. It was shown that there were fewer thromboembolic events on the ruxolitinib arm than in the best-available-therapy arm: 1.8 vs 8.2 in the RESPONSE trial per 100 patient-years of exposure. That’s definitely a signal, and from other studies in MPNs [myeloproliferative neoplasms], that ruxolitinib reduces thrombotic risk even though it may not have been shown as a clearly defined efficacy end point.

Expert perspectives on long-term management of patients with polycythemia vera, with regard for the risk of developing secondary MF or AML. 

Long-term Management Strategies for Patients With PV

There were 2 trials. One was called RESPONSE, and 1 was called RESPONSE-2. These were very similarly designed trials. The difference is that RESPONSE required patients to have splenomegaly, and RESPONSE-2 was done in patients without splenomegaly. These were phase 3 trials, large trials, done in a hydroxyurea-resistant and -intolerant population. The comparison was with standard therapy or best-available therapy, which ended up being hydroxyurea in a lot of these patients. Even though these were people failing hydroxyurea, many on the best-available-therapy arm got hydroxyurea simply because there aren’t good options in this setting. Of course, crossover was allowed after the primary end point had been assessed. As you might imagine, crossover was complete, with people switching over from the comparator arm to ruxolitinib [Jakafi].

In the RESPONSE trial, the 32-week primary end point, which was a composite of spleen volume reduction of 35% or greater, and hematocrit control to below 45% was achieved in 21% of patients on ruxolitinib and 1% of patients on the standard or best-available-therapy arm. If you broke down the primary end point into its components, then hematocrit control was achieved by 60% of the patients on ruxolitinib and 20% of the patients on the control arm. The spleen volume reduction was achieved by 38% of patients in the ruxolitinib arm and 1% of patients in the control arm.

Some other end points assessed at 32 weeks in this trial included symptom improvement as assessed by the TSS [Total Symptom Score] 50, the 50% or greater reduction in total symptom score. That was achieved by 49% of patients on the ruxolitinib arm and 5% of patients on the standard or best-available-therapy arm. The other end point assessed at this time point was the rate of CHR, or complete hematologic response, control of all 3 blood counts. That rate was 24% for the ruxolitinib patients and 9% for the patients on the control arm.

RESPONSE-2 was a very similar trial done in Europe. The only difference was that the patients didn’t have splenomegaly. The spleen volume reduction of 35% or more was not a relevant end point in this trial. It had remarkably similar results to RESPONSE, where the hematocrit control was 62% for ruxolitinib and 19% for best-available therapy. The complete hematologic response rate was 23% for ruxolitinib and 5% for best-available therapy. The 50% reduction in the TSS was 45% for ruxolitinib and 23% for best-available therapy. The spleen end point isn’t relevant to this trial. We have long-term follow-up from both trials. I’ll mention RESPONSE, which was the first trial. What’s reassuring and quite striking is that the benefit is sustained even at 5 years of follow-up, and no new adverse events show up. I’ll come to the adverse events in a bit. But the probability of maintaining these end points was quite impressive.

Seventy-three percent of patients in the ruxolitinib arm maintained their hematocrit control at 5 years, and 72% maintained that 35% or greater reduction in spleen volume, which is a robust duration of response and sustained response. The median duration of a complete hematologic response was 34 weeks. The probability of maintaining a complete hematologic response at 5 years was 55%. Speaking of adverse effects, 1 thing noticed in the RESPONSE trials were the occurrence of some excess basal cell and squamous cell carcinomas, more in patients with a history of the same. That’s something to be careful about. Another thing is the reactivation of [herpes] zoster, which was seen in about 6% of patients on RESPONSE. In my practice, I’ll give the shingles vaccine to all patients on ruxolitinib. Obviously, the response was very sustained with few discontinuations. In PV, ruxolitinib is much better tolerated from a cytopenia standpoint than in MF [myelofibrosis]. You don’t get the problems with cytopenia leading to interruptions and discontinuations that you might get a bit more of in MF, and that has to do with the disease biology.

In discussing the role of ruxolitinib in HU-resistant or intolerant PV, expert Prithviraj Bose, MD, highlights data from the RESPONSE and RESPONSE-2 clinical trials. 

Ruxolitinib in Uncontrolled PV: RESPONSE and RESPONSE-2 Trials

One issue we run into, as we saw in this case, is the development of hydroxyurea resistance or intolerance. [This involves] giving the patient a good dose, which has been defined as 2 g, but frankly it’s whatever the patient can tolerate for an adequate period, which has been defined as 3 months. This has all been defined by the ELN [European LeukemiaNet]. If you’ve given them whatever they can tolerate for at least 3 months, and you’re still not controlling their counts—they’re still needing phlebotomy, or their white blood cell count is still elevated—or if you’re achieving what you set out to achieve but they’re getting too cytopenic, for example, then the hematocrit is controlled but the ANC is too low, at less than 1 per mm3, or the platelets are less than 100 per mm3. If you’re making them cytopenic while trying to control their hematocrit, that would be intolerance. Similarly, if they’re getting leg ulcers, fever, and mouth sores, that would be intolerance of a different kind. These are all laid out nicely by the ELN. We can refer to those for a quick reference. They were also used in the trials that got ruxolitinib [Jakafi] approved for second-line use in the setting of hydroxyurea resistance or intolerance. Resistance would be where the myeloproliferation is continuing, despite an optimal dose of hydroxyurea.

In outpatient, not only were their symptoms never controlled, but neither was the hematocrit, in the sense that they kept needing phlebotomies. Certainly, phlebotomies didn’t get eliminated. Also, there was disease progression at 1 year when the spleen started to increase. There could be several ways of addressing this. One is to continue with the same hydroxyurea dose, which was 2000 mg at that point. One would be to increase it further. Another would be stop hydroxyurea and switch to something else. In this case, I would switch to something else because the patient has already been given 2000 mg for a decent period, 3 months, and they’ve never had phlebotomy elimination. They always had symptoms, and now their spleen is growing. It’s time to switch this patient. About 20% of patients could have hydroxyurea resistance or intolerance. In my experience is more intolerance than resistance. This patient is probably a bit of both.

There are a couple of options. Ruxolitinib is FDA approved for hydroxyurea resistance or intolerance, and then there’s interferon. I mentioned earlier that ropeginterferon alpha-2b [Besremi] is now approved for polycythemia vera. This drug is approved across lines of therapy, in the sense that there isn’t a line of therapy specified in the label. The label is for polycythemia vera broadly. There’s pegylated interferon, which was never specifically approved for PV but has been around a long time. It’s certainly quite effective. These are some other options we have for a patient who’s failing hydroxyurea. The NCCN [National Comprehensive Cancer Network] Guidelines were just updated in April 2022 to include ropeginterferon alpha-2b, given its recent FDA approval for low- and high-risk disease. It’s a choice in both settings.

However, what we’re talking about is hydroxyurea resistance and intolerance. This is where ruxolitinib has by far the most robust data. I alluded to this earlier to say that ropeginterferon alpha-2b hasn’t been studied in the setting of hydroxyurea resistance or intolerance in a strict sense. It has been studied in frontline patients and patients who’ve had a short duration of hydroxyurea and are neither failing it nor in complete response to it. That’s where that drug has been studied, but ruxolitinib has been studied very well in patients who have truly failed hydroxyurea by the ELN definition of resistance or intolerance.

Considerations for therapy when patients with polycythemia vera experience hydroxyurea resistance or intolerance.

Uncontrolled PV: Treating Patients With HU Resistance or Intolerance

This patient started with phlebotomy and aspirin, and then hydroxyurea was added when they had symptoms and they continued to need phlebotomy. In my practice, for a high-risk patient, I start with hydroxyurea. The hematocrit is always less than 45% based on the CYTO-PV trial. When I see them, if the hematocrit is higher than that, I’d probably order a phlebotomy along with prescribing hydroxyurea, but I typically don’t rely on just phlebotomy for a high-risk patient. I usually go straight with hydroxyurea.

The NCCN [National Comprehensive Cancer Network] Guidelines for MPNs [myeloproliferative neoplasms] were just updated in April 2022. There’s a new player on the market ropeginterferon alpha-2b was approved by the FDA in November 2021. This drug has a broad label for polycythemia vera [PV], and it’s mainly being studied in a frontline setting or a setting with minimal prior hydroxyurea treatment. I regard it more as a frontline drug than as a second-line drug. That’s a new treatment option as well to consider in today’s day and age.

The goal of treatment in PV, first and foremost, is to maintain that hematocrit under 45%, so that we reduce the risk of clots. Thrombosis is the main end point that we’re trying to avoid, and the treatments are tailored to reduce that risk. There can be rare bleeding as well, usually when the platelet count is extremely high. But that’s more of an issue in ET [essential thrombocythemia] than in PV. We’re trying to reduce the thrombotic risk for the patient. One of the primary means of achieving that is by getting the hematocrit under 45%. There are also some good data that suggest that controlling the white blood cell count below 11 per mm3 is important to that end.

With this patient we saw that the hydroxyurea dose had to be increased quite a bit. They started at 1000 mg and then went all the way up to 2000 mg. Some of it was symptom driven. That’s certainly reasonable because hydroxyurea can have some symptom benefit, although I don’t regard it as a great drug for symptoms. In my view, it’s more effective in controlling blood counts and preventing the risk of clotting, but sometimes that’s worth a try. Medications such as ruxolitinib [Jakafi], which we’ll come to later, are probably a lot better for symptom control.

Of course, patients with PV need to be assessed regularly. I typically see them every 3 months. However, in the beginning it can be a lot more frequent. You may need to see somebody every week or every 2 weeks while you’re getting that hematocrit stabilized, especially if it’s a low-risk patient in whom you’re not using a drug and just relying on phlebotomy. For high-risk patients, I typically start with a cytoreductive drug right off the bat. They may need to be seen pretty frequently initially.

As far as response goes, there are ELN [European LeukemiaNet] criteria, but these are more applicable for clinical trials. Frankly, in everyday patient management we’re using our clinical impressions of how well their symptoms are controlled and of course blood counts, with the goal being hematocrit under 45% at all times and, to the extent possible, white blood cell count less than 11 per mm3. The platelet count is less important to control because it doesn’t correlate with clotting risk for the most part. Some studies suggest that it might, but most studies don’t show a correlation between the platelet count and thrombotic risk. On the other hand, if the platelet count is extremely high—more than 1.5 million per mm3, there’s a bleeding risk. However, that’s much more of an issue in ET than in PV.

A comprehensive review of the treatment armamentarium for polycythemia vera, as well as strategies to monitor patients on therapy in this setting.

An Overview on Polycythemia Vera Management

™ program on case-based peer perspectives. Today’s topic is polycythemia vera [PV]. I’m Prithviraj Bose. I’m part of the leukemia faculty at [The University of Texas] MD Anderson [Cancer Center] in Houston, Texas. We’re going to start with the case of a 60-year-old man with uncontrolled PV, and then we’ll get into some of the discussion around the points that the case brings up.

This is a 60-year-old gentleman who presented in March 2020 with frequent itching, dizziness, and headache. Labs revealed a hemoglobin of 20 g/dL, hematocrit of 61%, an MCV [mean corpuscular volume] of 82 µm3, a white blood cell count of 11 per mm3, and a platelet count of 391 per mm3. The bone marrow revealed trilineage proliferation and pleiomorphic megakaryocytes. Molecular testing revealed the 

 V617F mutation, and the allele burden was 69%. The patient was diagnosed with polycythemia vera and was started on a baby aspirin, 81 mg per day, and phlebotomies.

In June 2020, 3 months after the diagnosis, the patient was seen again. He had had 3 phlebotomies in the prior 3 months and had continued symptoms. At that point, 1 g per day of Hydrea was added to the treatment plan. Fast-forward to September, 6 months after he was diagnosed, and he had had 6 phlebotomies since his visit in March. At this point, the hydroxyurea dose was increased to 1500 mg per day. In December, 9 months from his initial diagnosis, the patient was still dependent on phlebotomy. He a new complaint of pruritis, an emergent itching issue. The hydroxyurea at this point was increased to 2000 mg per day: 4 pills, 2 g per day.

In March 2021, a full year after he was initially diagnosed, he was still requiring phlebotomies. At this point, he started to complain of fullness after eating, an early satiety situation. The spleen at this point was palpable: 7 cm below the left costal margin. Clearly, we have a patient who has PV. He is started with phlebotomies and aspirin, and then hydroxyurea is added. The dose is progressively increased because of the issues we went over. We are a year out from diagnosis, and the spleen is big, phlebotomy is still required, and there are persistent symptoms. With that, we’ll get into our discussion on PV, starting with the diagnosis and the presentation.

Polycythemia vera is the most common myeloproliferative neoplasm. The criteria to diagnose PV have been updated. There are new criteria as of 2016. There are 3 major criteria and only 1 minor criterion. The first major criterion are the hemoglobin and hematocrit thresholds, which are slightly different in men and women. In men, it’s 16.5 g/dL or higher [for the hemoglobin]; in women, it’s 16 or higher g/dL. The second criterion has to do with the bone marrow biopsy. This didn’t used to be a major criterion, but now it is. The bone marrow biopsy typically shows, as in our case, pleomorphic megs, a panmyelosis picture with all 3 cell lines increased, as in our patient. The third major criterion is the 

 V617F mutation, which is found in 95% of patients with PV; another 4% will have an exon 12 mutation.

Those are your 3 major criteria. There’s 1 minor criterion, which is a subnormal or low EPO [erythropoietin] level. What’s needed for diagnosis are all 3 major criteria, which would satisfy the requirement, or the first 2 major criteria and the minor criterion. The order of the major criteria matters. The first 2 would be the hemoglobin/hematocrit and the bone marrow, along with the minor criterion, which is low EPO. This provision is there for the 1% or so who may not have the 

 mutation. Otherwise, the majority are going to be able to fulfill all 3 major criteria: the hemoglobin/hematocrit thresholds, the classic bone marrow appearance, and the JAK2 mutation.

Coming back to this patient, 1 of the first questions we face after we know the PV diagnosis, is what is the risk stratification? This patient 60 years old, but I would call this patient high risk, because we have traditionally considered 60 and older to be high risk, with younger than 60 being low risk. Regardless of age, if they’ve had a history of thrombosis, that makes them high risk. That wasn’t mentioned in our case. We’ll go just with the age, but because he’s 60, I’d call this a high-risk patient. The risk stratification hasn’t evolved, although there’s a lot of new information on the importance of white blood cells and how that may impact thrombotic risk and other risks. But the conventional risk stratification remains the simplistic classification based on age and prior thrombosis.

Expert Prithviraj Bose, MD, reviews standard practices in diagnosing and risk stratifying uncontrolled polycythemia vera in the context of a patient case.

Prithviraj Bose, MD | Authors

Articles

Unmet Needs and Future Directions in Polycythemia Vera Management

Long-term Management Strategies for Patients With PV

Ruxolitinib in Uncontrolled PV: RESPONSE and RESPONSE-2 Trials

Uncontrolled PV: Treating Patients With HU Resistance or Intolerance

An Overview on Polycythemia Vera Management

A Case of Uncontrolled Polycythemia Vera