"Besremi garners attention as a long-term treatment option for PV"

Professor Dae-young Kim of the Department of Hematology-Oncology at CHA Bundang Medical Center

Besremi is expected to expand treatment goals beyond controlling blood cell counts

Data for long-term response and administration possibilities have been accumulated

The treatment goal for polycythemia vera (PV) is shifting from simply lowering blood cell counts to considering long-term disease progression.

While conventional treatment focused on reducing thrombosis risk by lowering blood counts, recent goals have expanded to reduce disease-causing cells and maintain long-term stability.

Amid these changes, the interferon agent 'Besremi (ropeginterferon alfa-2b)' is drawing attention as a long-term treatment option. This is because Besremi reduces cells related to the underlying cause of the disease in addition to controlling blood counts, and evidence suggests the response can be maintained even after administration is discontinued following a certain period of treatment.

Professor Dae-young Kim of the Department of Hematology-Oncology at CHA Bundang Medical Center recently met with DailyPharm and stated, "In the treatment of polycythemia vera, even if the same blood cell counts are achieved, the impact of the treatment on the disease itself cannot be considered identical," adding, "Particularly for young patients who will need treatment for decades to come, treatment strategies must be considered from a long-term perspective."

The role of interferon agents highlighted amid the limitations of conventional treatments

Professor Dae-young Kim of the Department of Hematology-Oncology at CHA Bundang Medical Center

Polycythemia vera is a type of myeloproliferative neoplasm (MPN), a disease in which red blood cells abnormally and excessively proliferate in the bone marrow. In many cases, red blood cell counts increase along with white blood cell and platelet counts.

As blood cell counts increase, blood viscosity rises, increasing the risk of thrombosis. If a blood clot blocks a cerebral blood vessel, it can lead to a stroke, and if it blocks a blood vessel leading to the heart, it can lead to cardiovascular disease.

Some patients may also have the potential to progress to other hematologic diseases, such as acute myeloid leukemia (AML), in the long term.

For this reason, the treatment of polycythemia vera has traditionally focused on lowering blood counts, such as hematocrit levels. Representative methods include removing blood through phlebotomy or administering hydroxyurea to reduce overproduced blood cells.

However, these approaches have limitations for patients who require long-term treatment.

Phlebotomy requires patients to visit a medical institution regularly to have blood removed. During this process, iron levels decrease, which can lead to fatigue or lethargy. Hydroxyurea is inexpensive and available as an oral medication, but its primary role is limited to lowering blood counts.

Regarding conventional treatments, Professor Kim pointed out, "The focus has been on lowering immediate blood counts rather than controlling the underlying cause of the disease itself." Professor Kim said there are limits to preventing future disease progression or transition into other hematologic diseases.

Particularly in recent years, as health screenings and blood tests have become more widespread, relatively young patients in their 20s to 40s are also being diagnosed.

Professor Kim observed, "For young patients, as they must maintain socioeconomic activities while continuing treatment for decades to come, a strategy that considers long-term disease progression is necessary rather than short-term blood count control."

Recent changes in the treatment landscape of polycythemia vera reflect this point. This approach lowers the risk of long-term disease progression by reducing the variant allele frequency (VAF) of genes involved in disease pathogenesis, rather than merely lowering blood cell counts to a normal range.

Besremi is a pegylated interferon agent utilized in such treatment strategies. Conventional interferons can eliminate abnormal cells by activating immune cells, but they are limited for long-term use because of adverse events such as high fever and inflammatory reactions.

This therapeutic agent combines polyethylene glycol with interferon to allow the drug to act longer in the body. As a result, it is being evaluated as a treatment option suitable for long-term use by improving on the limitations of conventional interferon agents.

"Even with the same blood count, treatment status can differ"

Recently, a treatment concept has emerged that goes beyond simply lowering blood counts to suppressing disease progression in the long term. This approach involves lowering the variant allele frequency (VAF) of the JAK2V617F gene, which causes the disease, early on to reduce the risk of accumulating additional genetic abnormalities and long-term disease progression.

In addition, research continues to show that a higher JAK2 variant allele frequency is associated with poor prognoses, such as thrombosis or progression to myelofibrosis.

In a long-term follow-up study of Besremi, the molecular response (MR) at year 6 of treatment was 66.0% in the Besremi group and 19.4% in the control group. The JAK2 variant allele frequency also continuously decreased in the Besremi group, dropping to an average of 8.5% at 72 months.

Furthermore, among patients who showed a decrease in JAK2 variant allele frequency and molecular response, the study also confirmed an association with improved event-free survival (EFS), including thrombosis, disease progression, and mortality.

Professor Kim noted, "Even if the hematocrit levels of both a patient treated with hydroxyurea and a patient treated with Besremi drop below 45%, the treatment status of the two patients cannot necessarily be considered the same."

This is because even if the hematologic parameters are the same, the JAK2 variant allele frequency can differ. This means that even if the same hematocrit is achieved, the treatment's impact on the disease itself can differ.

Professor Kim explains that while the primary objective of hydroxyurea is to control blood cell counts and lower the risk of thrombosis, interferon agents like Besremi differ in that they reduce the JAK2 variant allele frequency and allow cells with normal genes to grow.

Many patients could also consider switching treatments.

According to Professor Kim, about 10% of patients are estimated to be refractory to hydroxyurea. Including patients who experience therapeutic efficacy but have difficulty continuing the medication due to adverse events, it is estimated that approximately 20% face difficulties in maintaining treatment.

Professor Kim stated, "There are patients who continue hydroxyurea treatment without any particular discomfort, but there are also cases where they undergo treatment while enduring persistent adverse events." For such patients, transitioning to other treatment options can be considered rather than maintaining the conventional treatment while enduring adverse events.

Professor Kim further added, "Age is also an important decision factor. For young patients with a relatively long treatment duration, long-term disease progression must be considered alongside immediate blood count control."

One year since reimbursement… Continued treatment for partial response patients must be considered

Besremi was listed for National Health Insurance reimbursement in South Korea last year. It is currently reimbursed as a second-line treatment for patients with refractoriness or intolerance to hydroxyurea.

Professor Kim believes the clinical changes since the reimbursement listing have been substantial.

Professor Kim evaluated, "I am currently prescribing Besremi for 8 patients with hydroxyurea refractoriness or intolerance, and I have confirmed a red blood cell count reduction effect in all of them. So far, there have been no cases of discontinuing administration due to adverse events."

Professor Kim added, "Until now, one of the biggest practical constraints in using Besremi in real-world clinical settings was the cost," and "Reimbursement listing has established conditions to prescribe it to patients who need the treatment."

On the other hand, suggestions were also made to view the current reimbursement maintenance criteria more flexibly to support long-term treatment.

Currently, Besremi reimbursement can only be maintained if a complete hematologic response (CHR) is achieved within 12 months post-treatment. A complete hematologic response requires meeting specific criteria for red blood cells, white blood cells, and platelets.

The issue is that some patients may not be recognized as achieving a complete hematologic response because their white blood cell or platelet counts do not meet the criteria, even though their red blood cells are sufficiently controlled. Their JAK2 variant allele frequency is decreasing.

Professor Kim pointed out, "I believe it is inappropriate to conclude a lack of therapeutic effect and halt reimbursement solely because a complete hematologic response was not reached at the 12-month mark."

He argues that because the European LeukemiaNet (ELN) also recognizes partial response as a pharmacological treatment effect, patients with partial response should have the opportunity to continue treatment, as should those with a complete hematologic response.

Professor Kim introduced, "Even in a 2-year follow-up of an investigator-initiated trial targeting domestic patients, the complete hematologic response achievement rate continued to increase after one year of treatment."

This implies that even if complete response is not reached at 12 months, the response can improve subsequently as treatment continues. It was also confirmed that in patients with partial response, the reduction in JAK2 variant allele frequency continued depending on treatment.

Possibility of discontinuation after 3 years of treatment… Re-administration criteria are a challenge

In the long term, a strategy of discontinuing drug administration after using the therapeutic agent for a certain period is also proposed as a possibility.

This is because reports describe cases in which some patients maintained their response even after treatment discontinuation, following a reduction in JAK2 variant allele frequency and complete hematologic response. Ultimately, the possibility of treatment discontinuation is being explored.

A recent study showed that even when patients who met certain criteria after 3 years of Besremi treatment discontinued it, more than half did not experience a rebound in red blood cells and maintained their response.

In this regard, Professor Kim emphasized its significance, saying, "If a stable condition is maintained for a long period without treatment, I believe it can be viewed as a concept close to a cure."

Research results are also emerging demonstrating that even in patients who relapsed after discontinuing treatment, re-administering Besremi can restore the therapeutic effect.

Professor Kim viewed this as a concept similar to the treatment discontinuation strategy in chronic myeloid leukemia (CML). In chronic myeloid leukemia as well, a method is utilized where some patients who have maintained an adequate treatment response for a long period can discontinue treatment. If they relapse subsequently, they are re-administered the previous therapeutic agent to elicit a response.

Consequently, there are also opinions that reimbursement for re-administration needs to be discussed in the future if a patient who discontinued administration after receiving Besremi treatment for 3 years requires treatment again. Professor Kim cited establishing specific application criteria through further data accumulation as a future task.

Professor Kim suggested, "Health insurance finances should also consider the long-term therapeutic effects, as well as the medical expenses and socioeconomic burdens that may occur after disease progression, rather than merely evaluating simple pharmaceutical costs."

In particular, because young patients have prolonged treatment periods, he deemed it critical to assess whether progression to thrombosis or other hematologic diseases can be mitigated and whether the disease can be stably managed over the long term.

Professor Kim's perspective is that Besremi should not remain simply a second-line treatment in the future management of polycythemia vera.

Professor Kim noted, "It is difficult to view hydroxyurea and Besremi as therapeutic agents of the same nature," pointing out, "While hydroxyurea is a treatment that controls blood counts, Besremi acts on the immune system and can even diminish the cells that are the root cause of the disease."

Professor Kim added, "In my opinion, Besremi is the therapeutic agent that can most closely approach the concept of a cure in polycythemia vera at present," and urged that Besremi should be considered from the initial treatment stage rather than remaining confined to first- or second-line treatment.