‘CML treatment needs to lower threshold for drug selection to manage adverse events’

Chronic myeloid leukemia (CML) was once considered a fatal disease.

With the advent of tyrosine kinase inhibitors (TKIs), however, it is now considered a cancer with which long-term survival is possible.

Nevertheless, as the treatment landscape evolves, survival rates, patient quality of life, and long-term treatment strategies have become more important.

First- and second-generation TKIs are now used as first-line treatments for CML, with each agent having a different adverse event profile. These adverse events significantly impact patients' quality of life. Even if these adverse events are not serious, patient adherence is bound to decrease if they cause persistent discomfort.

These changes affect not only the patient's quality of life but also the achievement of Major Molecular Response (MMR) and Deep Molecular Response (DMR) treatment goals. Despite the importance of managing these adverse events, however, drug replacement is often delayed or impossible in Korea due to reimbursement restrictions, which contributes to lower treatment success rates.

Korea Biomedical Review interviewed Professor Lee Sung-eun of the Department of Hematology at the Catholic University of Korea Seoul St. Mary's Hospital to learn more about the current CML treatment environment in Korea and to get her policy recommendations for optimal treatment strategies.

Question: How are TKIs used to treat CML patients in Korea, and how is each drug different in adverse events?

Answer: Currently, TKIs are the mainstay of CML treatment in Korea, with first- and second-generation drugs being used as first-line therapies.

Imatinib, a first-generation TKI, is the oldest and still available treatment. However, three second-generation TKIs (nilotinib, dasatinib, and radotinib) are primarily used as first-line treatments. Each agent has a different adverse event profile and is chosen based on the patient's condition.

For example, nilotinib is associated with a relatively high frequency of vascular thrombotic events, while dasatinib is characterized by adverse events related to pulmonary organs, including pulmonary edema and pulmonary arterial hypertension. Radotinib can also cause liver toxicity. There are also common adverse reactions, such as skin and musculoskeletal adverse reactions.

When these adverse reactions occur, the general approach is to adjust the dose and re-dose or change the agent if they do not resolve. However, in the case of serious adverse events affecting some major organs (such as the pancreas), it is difficult to re-dose the drug, and even relatively minor adverse events can reduce the patient's quality of life and often require a drug change.

In Korea. However, there is a restriction that once a drug is changed, it cannot be used again, which reduces treatment options. This can limit treatment flexibility if patients need to switch medications multiple times.

Q: Specifically, what constitutes a treatment failure that results in a drug change?

A: The definition of “treatment failure” includes intolerance due to an adverse event. However, the mere occurrence of a single adverse event does not necessarily indicate intolerance. In real-world clinical practice, a variety of factors, alone or in combination, can lead to a change in medication. For example, an adverse event may result in a patient not taking a high enough dose of a drug to achieve an adequate therapeutic response, or conversely, a patient may be using a drug normally and develop resistance due to a mutation.

Notably, recurrent grade 3 or higher non-hematologic adverse events despite appropriate dose reduction and optimal symptomatic treatment or persistent grade 4 or higher hematologic adverse events that make it difficult to continue using the drug may lead to a change in medication. These cases are defined as “treatment failure” once the medication is switched, the previous medication cannot be used again.

Q: If the drug cannot be switched again, there will likely be restrictions on the use of third- and fourth-generation drugs in subsequent treatments.

A: Let’s take acsiminib as an example. It won approval in Korea in 2022 and has been reimbursed since July 2023 for third-line or later treatment. Asciminib has a superior tolerability and safety profile compared to the existing bosutinib and is considered an advantageous option due to its lower risk of thrombosis than ponatinib, which is also reimbursed for the same third-line treatment. However, it has not been introduced in Korea for a long time, and it is possible that unexpected problems may occur after long-term use.

If patients are on asciminib for a long period and it is no longer available, they may be limited in their ability to switch back to a TKI that targets the original ATP binding site. This is especially burdensome in the domestic treatment setting, where change agents have less flexibility. Real-world clinical data on switching from asciminib to other TKIs is accumulating in Canada and the United Kingdom, with positive results. In Korea, real-world data is being collected, but the lack of sufficient cases will likely be a limiting factor in developing long-term treatment strategies.

Q: What are the criteria for drug selection in CML treatment, and what are the ultimate treatment goals?

A: In recent years, the most important factors in CML treatment have been adverse event management and patient quality of life. As survival rates have improved significantly, choosing the best drug for the patient, rather than just prolonging survival, has become the key to treatment. Notably, “optimizing treatment by carefully selecting the first drug” has become important, and researchers are using genetics and AI technologies to analyze patient-specific drug selection from an early stage.

One of the primary goals of CML treatment is to achieve major molecular response (MMR) and deep molecular response (DMR). MMR is a key indicator of long-term prognosis in many clinical studies, and patients who achieve it are reported to have better survival and disease progression control. Recently, the importance of DMR has been further emphasized. It has been shown that treatment-free remission (TFR) is possible if DMR is maintained for a certain period. In general, if a patient has been on a TKI for at least five years and has maintained DMR for at least two to three years, then drug discontinuation can be considered, and if successful, complete treatment termination can be expected.

Therefore, the goal of CML treatment is to achieve MMR and DMR quickly and reliably and, in the long term, near-complete remission with drug discontinuation. To achieve this, it is essential to select the optimal agent to maximize the therapeutic benefit while minimizing adverse events based on the patient's individual circumstances.

Q: We’re curious if there are any cases in Korea where TFR has been achieved and in which cases drug discontinuation can be attempted.

A: There are cases where TFR has been achieved in Korea, and it is determined based on international guidelines. TFR is not just a doctor's experience. Still, international guidelines, including the European Leukemia Network (ELN) and the U.S. National Comprehensive Cancer Network (NCCN), are the standard, and countries use them to decide whether to stop treatment.

According to the current ELN guidelines, TFR can generally be considered after five or more years of TKIs and two or more years of DMR of MR4.5 or higher or three or more years with MR4.0 criteria. However, the duration can vary depending on the depth of the reaction, and these criteria are becoming increasingly refined.

However, simply meeting the minimum requirements to attempt TFR is not enough. Each patient must be able to return for regular clinic visits after stopping treatment and be closely monitored for adverse events. The guidelines recommend monthly follow-ups for the first six months, every two months for up to one year, and every three months thereafter, and patients must be able to come in consistently.

The patient’s psychological readiness to try TFR is also important. Some patients may be anxious about discontinuing their medication, which can make it difficult to proceed with treatment interruption. Therefore, it is essential that the decision to consider TFR is made carefully and in consultation with the patient.

Q: Do you believe the domestic treatment environment is adequate to meet the goals of CML treatment?

A: Korea has an advantage in that all TKIs are covered by insurance. However, it also has limitations because physicians have limited freedom in their treatment strategies. While initial drug selection and subsequent strategic choices are critical to achieving treatment goals, it will take time for these treatment strategies to be fully implemented in Korea.

Therapies are now only available within insurance coverage. Previously, only imatinib was available as a first-line treatment and second-generation TKIs were reimbursed only for second-line treatments. However, most patients are now using second-generation TKIs as first-line treatment. The problem is that when patients switch to a second-generation TKI and need to switch to another second-generation TKI, they are sometimes denied reimbursement for not using imatinib, even though the science is precise.

In addition, the reimbursement criteria for asciminib emphasizes the phrase “only acceptable in the absence of the T315I or V299L mutation,” which has led to increasing benefit reductions without considering individual patient responses. There is a scientific premise that patients who respond very well do not need these tests, but this is not fully recognized.

As a result, one specific phrase in the reimbursement criteria is leading to cuts that don't consider the individual circumstances of the patient, and we have submitted a proposal to a related academic society to address this issue. However, the long time it takes to resolve the issue is a major limitation, which means that the current treatment environment in Korea is not optimized for achieving CML treatment goals.

Q: Do you have messages for related parties?

A: There is always a gap between what patients want and what doctors think is possible. Doctors usually explain that patients can live a normal life, work, and socialize, but patients often don't feel that way.

Notably, the most common complaint from patients is low-grade adverse events (CTCAE Grade 1-2). Even these mild side effects can significantly impact daily life and reduce quality of life, requiring a more flexible approach to treatment. To address this, treatment environments must be created that ensure patients have the option to change or revert to a drug if needed. This flexibility would greatly benefit patients.

I also believe that research into personalized medicine needs to be further developed and that healthcare providers should develop optimal treatment strategies for each individual.