Polycythemia vera (PV) is a rare, intractable blood cancer in which a somatic mutation in the bone marrow causes the bone marrow to function abnormally and overproduce red blood cells.

The abnormal production of blood cells in the bone marrow causes the blood to become thick, which increases the risk of cardiovascular complications, such as thrombosis and embolism. This condition can progress to malignant cancers, such as myelofibrosis and acute myeloid leukemia.

While hydroxyurea is widely used as the first-line standard of care globally due to its effectiveness in preventing thrombosis, reducing mortality, and low cost of treatment, there is a high unmet need for follow-up treatment options. The disease cannot be cured, and resistance can lead to difficulty controlling hematocrit, which can reduce life expectancy to one to two years due to thrombosis or cardiovascular complications.

“Interferons” have been used to treat PV for decades. The introduction of “Besremi” (ropeginterferon alfa-2b), a third-generation mono-pegylated interferon with excellent tolerability and ease of administration, has moved the treatment of PV into the realm of personalized medicine.

Recently, there have been several reports of patients with PV treated with interferon maintaining a complete hematologic response (CHR) for more than two years, reducing their JAK2V617 mutation burden to less than 10 percent, and maintaining a CHR and reduced mutation burden for many years after interferon treatment is discontinued, raising the possibility of a potential operational cure.

Korea Biomedical Review spoke to two world-renowned experts in myeloproliferative neoplasm -- Professor Jean-Jacques Kiladjian of the Department of Hematology at St. Louis Hospital, France, and Professor Hans Carl Hasselbalch of the Department of Hematology at Zealand University Hospital, Denmark, to learn about the changing landscape and outlook for the treatment of PV, and the clinical value of Besremi within it.

KBR: How has the treatment of PV changed?

Hasselbalch: Hydroxyurea, the current treatment for PV, is effective in preventing blood clots from forming in the brain, heart, and lungs. However, it does not directly target the malignant stem cells, and once the treatment is stopped, the blood clots return to pre-treatment levels within a few days. Furthermore, hydroxyurea was not suitable as a long-term treatment because long-term use could lead to other conditions, such as acute myeloid leukemia.

Interferons have also been used to treat PV for decades. Interferon has the advantage of achieving a progressive complete hematologic response on average in a matter of months and can target and eliminate malignant stem cells. It is also a treatment option that can be tailored to the individual patient, making it a personalized medicine type of treatment.

Interferons have been used in Denmark for 20 to 30 years, first with interferon alfa-2b, used three times a week, and then with pegylated interferon alfa-2a, which could be used once a week. Later, Besremi was introduced, allowing for once-weekly dosing every two or four weeks, improving tolerability and adherence.

KBR: We understand that Professor Kiladjian recently conducted a study that suggested a "potential cure" for PV.

Kiladjian: We didn't set out to stop treatment from the beginning. We were doing a cohort study of 400 patients who had been on treatment for more than three months, and we realized that a large proportion of patients had a high response to treatment. We saw common characteristics in those patients as their physicians lowered the dose and ultimately stopped treatment.

Through multivariate analysis, we could identify two factors. One was that patients had been on treatment for at least two years before discontinuation, and the other was the characterization of their molecular response. Patients who stopped treatment with less than 10 percent of JAK2V617F mutations were more likely to maintain a consistent therapeutic response after discontinuation and were more likely to remain on treatment for more than five years. The first patient to discontinue treatment 13 years ago is still alive and well today, with no treatment restart.

These benefits clearly differentiate interferon from other PV treatment options, such as hydroxyurea and ruxolitinib. With hydroxyurea, no matter how long you take the treatment, your blood counts will rise again within 10 days if you stop the treatment, whereas with interferon, under certain conditions, you can expect a consistent treatment effect even after stopping the treatment.

Hasselbalch: Most importantly, when there is a treatment that can lower the burden of the JAK2V617F mutation, such as Besremi, it is important to prioritize what therapeutic benefit can be expected. Most patients show a trend toward a decrease in JAK2V617F mutation burden after interferon treatment. As a result, interferon is a treatment that can prevent the disease from worsening. As with other cancers, if left untreated, myeloproliferative tumors can progress to metastasis and cross the river of no return. It's important to start quantitative testing from the time of diagnosis so that if treatment is needed, it can be started as soon as possible.

I personally perform quantitative analysis for the JAK2V617F mutation three times a year on my patients from the time they are first diagnosed to determine the rate. This is important because the detection rate of the JAKV617F mutation allows us to prepare for the disease in the future. Patients with more than 50 percent of JAK2V617F mutations have been shown to have a higher burden of severe cardiovascular disease, as well as myelofibrosis. This quantitative analysis will also help future studies determine the relationship between patient-specific characteristics and the declining burden of JAK2V617F mutations.

KBR: Does this mean that precision medicine will become possible, with prognosis and treatment strategies based on molecular response status?

Hasselbalch: In the field of myeloproliferative neoplasms, we are also defining the concept of microscopic residual disease (MRD), and we are entering an era where we can take a break from treating PV. This means that patients can live a healthy, normal life for many years, with regular outpatient visits and tests as needed, rather than long-term treatment as in the past.

The health and economic benefits of this will be significant, including the ability to take years off from treatment and resume treatment as needed to minimize tumor burden and disease morbidity. Furthermore, I am confident that the future for patients will be much brighter than it is today.

Kiladjian: Interferon is the only treatment that can normalize bone marrow. In the past, doctors in the Nordic countries have shown that the use of interferon in patients with PV has resulted in bone marrow normalization. Interferon is not just a treatment that improves numbers; it improves the course of the disease, including normalizing blood counts, improving symptoms, and reducing the burden of the JAK2V617 mutation. As a result, we believe it is a treatment that can halt the progression of the disease and allow for a dosing break.

KBR: Hydroxyurea is used as a first-line treatment in most countries. Are there any attempts at sequential treatment strategies or combinations?

Hasselbalch: We are conducting a study in Denmark on combination therapy. The idea is to quickly lower blood counts with hydroxyurea and then add interferon for a synergistic effect. A study in Sweden showed that patients with PV tend to have an increased risk of blood clots in the first three to six months of treatment. Since hydroxyurea and interferon are thromboprophylaxis agents, we believe that the combination of the two agents may reduce the risk of early thrombotic events.

Kiladjian: Interferon has a pro-inflammatory effect when used in the acute phase, which may increase the inflammatory response somewhat and may be associated with some risk of thrombosis. However, with long-term use, the pro-inflammatory tendencies disappear, and malignant stem cells are rapidly depleted. In addition, interferon requires testing for autoimmune disease, heart, or eye disease before starting, so you may want to consider starting treatment with hydroxyurea first to lower blood counts and reduce the risk of thrombosis before starting interferon.

KBR: With all the amazing advances in PV treatment in recent years, and potentially even a cure, do you have any advice for patients considering treatment amidst the rapid changes?

Kiladjian: I would encourage people to think of treating PV as a marathon, not a 100-meter sprint. Failure to start interferon treatment early on is not a recipe for disaster. It's okay to treat with hydroxyurea for three to four years and then switch to interferon when interferon becomes more accessible. Healthcare providers will also help patients lower their risk of cardiovascular disease and maintain their quality of life until interferon treatment becomes available, ultimately helping them reach a potential cure.

In the meantime, health authorities should work to raise awareness about Besremi's utility and tolerability, which is not the case for other classes of therapies, and to ensure patient access to treatment. The PV treatment landscape has already made significant progress. This has allowed for treatment interruption, which was previously thought impossible. Besremi is a pharmacodynamic improvement over existing interferon agents, and it offers many advantages in terms of tolerability and overall disease management with fewer doses.

Hasselbalch: For patients, advances in interferon therapies, especially with the advent of Besremi, have made the treatment horizon and their outlook for life much brighter.

On the other hand, I think health authorities need to be a little more vigilant about myeloproliferative tumors. Today, myeloproliferative neoplasms are no longer a rare disease. In Denmark, there are currently around 4,500 patients with the disease, and it is estimated that there are around 10,000 more undiagnosed cases. It is believed that many undiagnosed patients have blood clots in the brain, lungs, and heart but do not think of myeloproliferative tumors and go to other departments, such as neurology and cardiology, for treatment.

For example, the percentage of ischemic stroke patients with the JAK2V617F mutation is as high as 11.2 percent. If they are diagnosed with PV and treated with interferon, they can restore normal blood counts, but they are still being brought to the hospital once or twice a year without knowing they have PV.