Navigating Resistance and Intolerance in High-Risk Polycythemia Vera
Key Takeaways
- Suboptimal response and intolerance to hydroxyurea at maximum tolerated dosing, plus ongoing symptoms and cardiovascular risk, define a clear trigger to transition to second-line cytoreductive therapy.
- Ropeginterferon alfa-2b requires gradual onset (median ~7 months) and should be started with concurrent hydroxyurea taper to prevent rebound cytoses and thrombotic risk.
In this discussion, led by Mojtaba Akhtari, MD, a medical oncologist at Loma Linda University Medical Center in Loma Linda, and participants, the case of a 66-year-old patient with high-risk polycythemia vera (PV) is discussed.
The discussion focuses on the rationale for transitioning to second-line cytoreductive therapy, addressing the role of rpegintereron-alfa-2b (Besremi). Participants reviewed the pivotal data from the PROUD-PV and CONTINUATION-PV trials.
This is part 2 of a 2-part discussion. Part 1 can be found here:
CASE SUMMARY
A 66-year-old woman with high-risk polycythemia vera (PV), shortness of breath, and occasional sharp chest pain presented with laboratory findings of:
- Hematocrit: Increased at 47%
- White blood cell count: 12,500
- JAK2-V617F mutation variant allele frequency of 65%
Medical history: hypertension and obesity
Initial Management:
- Hydroxyurea (Hydrea), 1000 mg daily
- Cardiovascular risk factor management
- Regular monitoring plan established
DISCUSSION QUESTION
- What would be your next step for this patient?
Mojtaba Akhtari, MD: This is a 66-year-old patient with high-risk polycythemia vera (PV) on 1000 mg of hydroxyurea daily. Despite therapy, the disease is suboptimally controlled with a persistent hematocrit of 47% and a high JAK2 burden of 65%. The patient is intolerant to hydroxyurea escalation due to significant toxicity such as oral ulcers, severe skin reactions, and declining platelets, effectively reaching a maximum tolerated dose with an inadequate response. Given the presence of active symptoms, ie, chest pain, ongoing cardiovascular risk factors, and failure on first-line cytoreductive therapy, this patient is a candidate for a second-line agent. Dr Goldenson, what is your take?
Ben Goldenson, MD: This is a patient who I would offer ropeginterferon-alfa-2b-njft [Besremi], although hydroxurea is also a good option. I probably have a preference for ropeginterferon because it has more disease-modifying activity.
Akhtari: Regarding the current regimen: if we increase the dose of hydroxurea, the platelet, the platelet count will obviously worsen, and the patient has already developed mouth ulcers. Simply maintaining the current dose doesn't address the underlying problem.
Therefore, we should stop hydroxurea and initiate another option. Starting a JAK inhibitor is a good choice, as is ropeginterferon. The key consideration with ropeginterferon is that you cannot stop hydroxurea abruptly; you must taper it over a period of 12 to 13 weeks. You should start the ropeginterferon at 50 µg and gradually taper the hydroxurea down. If you stop hydroxurea immediately upon starting the new therapy, the blood counts could spike, which would put the patient at risk.
Mohammad Ziari, MD: How do you evaluate the level of the JAK2?
Akhtari: You can determine it qualitatively or quantitatively. If you require a quantitative approach, I usually send it to the major laboratory testing companies, such as LabCorp or Quest, and they do it for you. I usually request it about every 3 months, definitely not more than every 3 months.
Misagh Karimi, MD: Are you going to act on it if you’re going to check the titer?
Akhtari: That’s a good question. But other oncologists monitor it every 3 months, similar to how we follow chronic myeloid leukemia. The question is, should you increase the dose based on the result? Nobody knows; we don't have data to support that. What would you do if you saw the numbers change?
Goldenson: Yeah, I think for the most part, it’s done for reassurance. But there is some data showing that about 10% of patients can actually clear the JAK2 mutation and eventually stop treatment.1
Karimi: Stop treatment? So if the mutation clears, they can come off it?
Goldenson: Exactly. The study wasn't long-term, maybe 5 years, but some patients were able to discontinue therapy.1
Akhtari: At what point do you typically switch from hydroxyurea to a different cytoreductive therapy?
Karimi: Usually after both intolerance and resistance or after failure to achieve specific blood count targets within a specific number of months of reaching the maximum tolerated dose.
Akhtari: Turning to the PROUD-PV (EudraCT 2012-005259-18) and CONTINUATION-PV (EudraCT 2014-001357-17) studies, which were phase 3 trials conducted in 48 clinics across Europe.1 Patients were randomly assigned 1:1 to receive ropeginterferon alfa-2b or hydroxyurea. Patients were followed for between 3 to 5 years. The primary end point was complete hematologic response, a hematocrit below 45%, a platelet count below 400,000/ µL, a shrinking spleen as determined by imaging by month 12.
Ziari: Is it based on high risk or low risk?
Akhtari: These are high-risk PV patients—previously on hydroxyurea with a history of thrombotic events. Looking at complete hematologic response and molecular response at 12 months, the key point is that ropeginterferon takes time to work; the median time to complete response is about 7 months. In year 6 of treatment, 81.4% of patients maintained hematocrit below 45%, compared with 60% in the control group. Event-free survival over 6 years was better with ropeginterferon alfa-2b. Complete hematologic response rates at 12 and 36 months were also superior. Regarding the JAK2 V617F allele burden, the data indicate that an increase in allele burden correlates with higher risk.
The most common toxicity is influenza-like illness and arthralgia. I've also seen nasopharyngitis, and interestingly, some patients report a sensation of something in their throat. Diarrhea can occur, and it may also cause cytopenia, so that's something to keep in mind.
Monitoring is important. Initially, blood tests should be done weekly, then every 2 weeks, and eventually every 2 months once the patient stabilizes. The good news is that 95% of adverse events are grade 1 or 2. The most common serious adverse events include urinary tract infection [8%], transient ischemic attack [6%], and depression [4%]. Depression is also the most common reason for discontinuation, at 8%.
In my own experience, I've had a patient develop a skin rash. I've also seen both hypothyroidism and hyperthyroidism, so it's worth monitoring thyroid function as well.
What about your experience?
Goldenson: I’ve seen the flu-like symptoms but mostly at higher doses.
Akhtari: What is the maximum dose that you’ve used?
Goldenson:I’ve had patients up to 500 µg, but a good number of patients will back off eventually.
Akhtari: I’ve had patients up to 400 µg. And I agree, the majority of patients will have better counts. They come under control.
