Exploring Early Cytoreductive Approaches Beyond Phlebotomy in PV

The main goal in managing the patient with low-risk polycythemia vera (PV) is to maintain hematocrit levels below 45% to prevent thrombosis, reduce symptom burden such as fatigue and itching, and slow progression. Targeted agents such as ropeginterferon alfa-2b (Besremi) offer early- and second-line cytoreductive options compared with phlebotomy.

Mojtaba Akhtari, MD, a medical oncologist at Loma Linda University Medical Center in Loma Linda, and participants, discussed the role of ropeginterferon in the patient with low-risk disease.

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CASE SUMMARY

A 42-year old woman who is asymptomatic at diagnosis presents with initial laboratory findings of:

• Hematocrit: 62%
• Hemoglobin: 17.2 g/dL
• White blood count: 9.8 × 10⁹/L
• Platelets: 450 × 10⁹/L
• Hematocrit: 3 mU/mL (low)
• JAK2 V617F: positive

Risk Assessment

1. Low-risk category
2. Age < 60 years
3. No prior thrombosis

Initial Management

• Phlebotomy (target hematocrit < 45%)
• Aspirin 81 mg/day
• CV risk factor management
• Monitor for progression

DISCUSSION QUESTIONS

• What patient and clinical factors do you consider in your initial choice of treatment for patients with low-risk polycythemia vera (PV)?
  • What are your goals for treatment?
  • How aligned are your goals and your patients’ goals?

• What factors trigger an escalation in monitoring or initiation of cytoreductive therapy?

Mojtaba Akhtari, MD: What patient and clinical factors do you consider in your initial choice of treatment for patients who are at low risk? What are your goals of treatment?

Ben Goldenson, MD: We want to get the hematocrit below 45% and white blood cell count below 10 × 10⁹/L. It might be difficult to convince a patient who is asymptomatic and low risk to take injections. But the injections can be reduced to once a month, after 12 months.

Akhtari: Yes, after 12 months, the number of injections can be reduced. If the patient is in good shape, it can be reduced earlier, too, according to the package [insert]. Patients can give the injection to themselves. I usually suggest they give it on Friday night or Saturday, take acetaminophen [Tylenol] or Benadryl a half-hour before an injection, have the injection, and go to bed.

Vandana Agarwal, MD: The patient has to be JAK2-positive in order to give ropeginterferon alfa-2b-njft [Besremi]. What about secondary polycythemia?

Akhtari: That’s a good point. In primary PV, our goal is to get hematocrit below 45%. In secondary PV, we usually want to get the hematocrit below 50%, but I have patients with sleep apnea or they might be on testosterone. Sometimes, they are symptomatic.

For men who see their primary [care physician], they might say they feel fatigue, or “It’s interfering with my job.” The physician checks their testosterone [levels] and it’s mildly low. The patient gets put on testosterone. They end up with erythrocytosis. It’s very common. So now, you can’t get them off testosterone. So they are on testosterone [which increases hematocrit levels].

Umair Ghani, MD: Then you can give them iron infusions and recycle.

Akhtari: I have done that and it’s a vicious cycle.

Barbui et al¹ evaluated ropeginterferon alfa-2b vs phlebotomy in patients with low-risk PV. The study involved 127 patients with a JAK2 V617F or exon 12 mutation who were randomly assigned to ropeginterferon [n = 64] vs phlebotomy [n = 64]. Primary end points were maintaining hematocrit less than 45% over 12 months in the absence of progressive disease.

Pamela Miel, MD: I have a question. How do you switch from hydroxyurea [Hydrea] to ropeginterferon?

Akhtari: Excellent question. Ropeginterferon is a targeted therapy, not chemotherapy. It works gradually. You start the patient on 50 μg over 12 or 13 weeks, then you gradually taper down the hydroxyurea.

The study [here] looked at response rate, hematocrit control, disease progression, and number of phlebotomies. [The agent] can cause transaminitis. When you hit the JAK/STAT pathway, patients can develop hypercholesterolemia and hypertriglyceridemia. It’s a good idea to have a baseline lipid panel and check it over 3 or 4 months. Also, flu-like symptoms are common.

CASE DISCUSSION

Considering the Low-PV and CYT0-PV study data (NCT03003325):²

• What is the goal of hematocrit level that you treat to?
• What is the overall role of ropeginterferon alfa-2b for low-risk PV?
• What is your primary criteria for initiating cytoreductive therapy in a newly diagnosed low-risk patient with PV?

Akhtari: Let’s talk about the goal of hematocrit and the role of ropeginterferon. What do you think, Dr Karimi? Progressive leukocytosis or progressive thrombocytosis? If the spleen continues enlarging, does the patient undergo frequent phlebotomy? What if the patient is intolerant of phlebotomy?

Misagh Karimi, MD: All of the above.

Akhtari: Yes, yes, all of the above. You are right. You know that the phlebotomy needle is big. I’ve seen patients pass out and faint when they see the needle.

Getting back to the patient, the patient has had routine follow-up visits for 8 years. Now, the hematocrit is 45% and the patient presents with a left lower leg deep vein thrombosis [DVT] and increased fatigue. What’s your next step?

Mohammad Ziari, MD: I would not put the patient on hydroxyurea

Akhtari: Yes, I would not put the patient on hydroxyurea. What about a clinical trial? Do we have clinical trials at UCI [University of California Irvine] for PV?

Ziari: We have a lot of trials. I’m not sure about this specifically.

Akhtari: Dr Goldenson, do you have clinical trials for PV?

Goldenson: We don’t. We have trials for myelofibrosis but not PV.

Ghani: Dr Akhtari, what if it was a provoked DVT. For example, if it was post-operative? What if it wasn’t PV that’s causing it?

Akhtari: Then, no provoked DVT, you would treat for 3 to 6 months. Yes, that’s common sense. What do you think, Dr Goldenson?

Goldenson: That’s a hard question because you don’t know how the PV is contributing. This is a high-risk condition for thrombosis. I would consider doing a limited treatment, but it’s more of a reason to be on cytoreductive therapy. I would recommend ropeginterferon because you have multiple benefits.

Ghani: After the first event [of DVT], you’re at high risk of having a second event.

Akhtari: Yes. Is this a real patient or hypothetical?

Ghani: Hypothetical.

Akhtari: That’s good. So let’s say it’s a 45-year-old patient with low-risk PV who takes aspirin, but needs surgery because he’s a soccer player and broke his tibia. He’s in a cast but develops a new blood clot. He needs to take apixiban [Eliquis]for 3 to 6 months. What was his hematocrit? Was it controlled?

Ghani: It’s controlled.

Akhtari: This is a tough one, but in my mind, this is not progression because there is a reason for the clot.

DISCLOSURE

Dr Akhtari has no relevant financial relationships to disclose.

REFERENCES

1. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial. Lancet Haematol. 2021;8(3):e175-e184. doi:10.1016/S2352-3026(20)30373-2

2. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon versus standard therapy for low-risk patients with polycythemia vera. NEJM Evid. 2023;2(6):EVIDoa2200335. doi:10.1056/EVIDoa2200335