Polycythemia vera (PV) is a rare blood cancer that causes an overproduction of red blood cells due to bone marrow malfunction. Gene mutations, including JAK2 mutations, cause excessive production of red blood cells, leading to death from cardiac complications, such as thrombosis and embolism. About 20 percent of patients progress to myelofibrosis or acute myeloid leukemia.

Hydroxyurea, the only health insurance-covered treatment for PV in Korea, effectively prevents thrombosis and reduces mortality.

However, the drug has limitations, as it does not provide a fundamental cure for the disease. In particular, there is a significant clinical unmet need for follow-up treatment options, as hematocrit control is difficult in the event of resistance to hydroxyurea therapy, and life expectancy could plunge to one or two years due to thrombosis or cardiovascular complications.

In Korea, Novartis' Jakavi (ruxolitinib) expanded its indication to treat PV in November 2016 and tried unsuccessfully to enter the reimbursement system twice. Most recently, PharmaEssentia’s Besremi (rofeginterferon alfa-2b), which won approval in October 2021, submitted a reimbursement application to the Health Insurance Review and Assessment Service (HIRA) earlier this year and is awaiting its review.

Korea Biomedical Review spoke with Jung Chul-won, professor of hematology-oncology at Samsung Medical Center, to learn about the treatment of PV, unmet clinical needs in Korea, and the need for Besremi to get coverage.

Question: Because PV is rare blood cancer, little is known about it. What is PV?

Answer: PV is caused by mutant JAK2 cells in the blood-producing bone marrow that cause an overproduction of not just red blood cells, as the name implies, but all blood cells, including white blood cells and platelets.

Overproduced blood cells are so viscous that they can get stuck in the blood and block blood vessels in the brain or heart. This can lead to vascular complications, such as thrombosis and myocardial infarction. It is a deadly disease that can progress to malignant cancers, including myelofibrosis and acute myeloid leukemia, if gene mutations persist. Korea is estimated to have about 5,000 patients.

Q: How PV is diagnosed?

A: As regular health checkups are popularized, blood tests often reveal suspected blood disorders, which are confirmed by further tests. Especially in the case of blood diseases, the fluctuations of red blood cells, white blood cells, and platelets are very wide, so it is possible to diagnose them quickly if checked periodically. Therefore, it is important to have regular health check-ups to diagnose the disease early and treat it quickly.

Q: What is the current standard treatment for PV?

A: Treatment strategies vary depending on the risk group. We categorize patients over 60 or those at high risk of developing vascular complications as high-risk. We treat low-risk patients who don't fall into this category with aspirin or try phlebotomy. In addition, we treat high-risk patients with hydroxyurea, which inhibits blood cell proliferation.

Hydroxyurea has the advantage of significantly reducing the incidence of vascular complications. However, the drug is limited as it is not a curative treatment. In addition, although there is individual variation, some patients experience adverse events, including skin mucositis, ulcers, and gastrointestinal upset, with hydroxyurea therapy that prevent them from continuing treatment. In particular, about 10 percent of patients develop resistance or intolerance after hydroxyurea treatment, leading to a statistically low survival rate of only one to two years due to vascular complications.

Q: What is the follow-up treatment strategy for patients who fail hydroxyurea therapy?

A: Two treatment options can be considered -- Besremi and Jakavi. Besremi is a long-acting interferon agent that stimulates immune cells to eliminate abnormal hematopoietic cells in the bone marrow. Besremi was associated with higher complete hematologic response rates than hydroxyurea, as well as significantly improved event-free survival and lowered risk of disease progression and relapse. Based on these results, it is recommended in the NCCN guidelines as the first- and second-line treatment option for PV.

Jakavi has a mechanism of action that blocks the signaling pathway of the JAK2 gene. It effectively improves symptoms and quality of life in patients resistant to hydroxyurea therapy or with adverse events. However, further clinical evidence is needed to determine its potential for treating the underlying cause of PV, including preventing disease progression.

Q: Despite the poor prognosis, there are no reimbursable follow-up treatment options for patients who fail hydroxyurea treatment.

A: Patients who cannot be treated with hydroxyurea are continuously exposed to the risk of vascular complications and urgently need improved access to new drugs. Despite the need for new treatments, many patients cannot afford them. I can understand somewhat that the government remains reluctant to provide insurance for the therapy because it has insufficient data with more than 10 years of follow-up survival and failed to demonstrate visible cost-effectiveness compared to hydroxyurea.

However, patients who do not have access to hydroxyurea have severe symptoms, have difficulty with their daily activities, and remain at risk of vascular complications. They don't know when this will happen to them. In addition, the number of these patients is small regarding the incidence in Korea. Considering all these, the clinical community hopes the government will recognize and consider the need for reimbursing follow-up treatments.

Q: What will you suggest to improve the treatment of hematologic cancers in Korea?

A: The Cancer Disease Review Committee currently applies similar criteria to evaluating reimbursement for hematologic and solid cancers. However, hematologic cancers are rare, and data demonstrating survival benefits are difficult to obtain. Considering the unique nature of the disease, I think it is necessary to improve the methodology for evaluating the appropriateness of reimbursement by, for instance, establishing a separate committee to evaluate the appropriateness of reimbursement for blood cancer treatments or focusing on the opinions of blood cancer experts.