Changes to the treatment settings have been brought to Mantle cell lymphoma (MCL) with the launching of new treatments like BTK inhibitors and implementing reimbursement.

As the 2nd-generation BTK inhibitors are introduced, treatment options have been broadened for relapsed or refractory MCL, where treatment options have been limited to 1st-generation BTK inhibitors.

During a meeting with Daily Pharm, Dr. Youngwoo Jeon, a Professor in the Department of Hematology at Yeouido St Mary's Hospital, who runs the only Lymphoma and Cell Therapy-Research Center in South Korea, emphasized the need to discuss ways to effectively utilize treatment options.

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 5% of all NHL cases. MCL shows aggressive clinical features.

Unlike typical lymphoma that starts in lymph nodes, MCL occurs in organs where lymph nodes are not located. Patients often transfer from dermatology, oncology, and gastroenterology to hematology.

Five years ago in South Korea, the annual new patient number was about 80. Now, that there are about 100-110 new patients each year.

"According to international classification standards, extranodal T-cell lymphoma is typically considered indolent; however, once it surpasses a critical threshold, it can proliferate rapidly, like DLBCL, and requires immediate treatment," Dr. Jeon said. "Even if the disease initially progresses slowly, the short time between diagnosis and treatment means clinicians on the front lines inevitably perceive it as aggressive."

In the case of MCL, the development of new treatment options, including standard therapies, has been slow, and treatment protocols or strategies have only been established relatively recently. As a result, treatment approaches have been sporadic and often based on available economic discretion, implying that patients have been treated drugs designed for other types of lymphoma treatments.

Previously, combination treatments such as CHOP (rituximab+cyclophosphamide/doxorubicin/vincristine/prednisone) were primarily used. Patients with poor ECOG were administered treatments that have lower-toxicity, such as follicular lymphoma treatments like R-CVP (rituximab+cyclophosphamide/vincristine/prednisone).

In addition to these options, patients have the choice to pay for BR treatment (bendamustine+rituximab) out-of-pocket.

"Expanded option to include BTK inhibitors is regarded favorable, 2nd generation with reduced side-effects gains attention"

The remaining issue lies in the relapse and treatment resistance seen in MCL. Many patients present with a poor prognosis at diagnosis, and given the nature of indolent lymphomas, which are notoriously difficult to cure, the sequencing of treatments becomes increasingly critical.

Dr. Jeon explained, "Full recovery is challenging for indolent lymphomas like MCL. Thus, we adopt a strategy similar to that used in treating chronic lymphocytic leukemia, focusing on maximizing progression-free survival (PFS). Moreover, because relapse is frequent, it is difficult to aim for a cure from the very first treatment line, so we carefully plan the treatment sequence for when the disease relapses."

In response to these unmet therapeutic needs, BTK inhibitors have emerged. In addition to the 1st-generation agents, a 2nd-generation treatment, like Brukinsa (zanubrutinib), has been introduced.

Since June 2024, reimbursement for Brukinsa has been expanded to include its use as monotherapy for patients with MCL who have received at least one prior treatment.

Dr. Jeon analyzed, "The introduction of oral targeted anticancer agents, such as first- and second-generation BTK inhibitors, has greatly improved patient treatment convenience. Under conventional cytotoxic chemotherapy, patients typically endured cycles of deterioration and improvement over more than a year of hospital admissions, often leading to death. Because patients can self-administer the medication and only need to manage side effects, treatment accessibility has been significantly enhanced."

In fact, the 1st-generation BTK inhibitor, Ibrutinib, has shown outcomes that surpass those observed in clinical trials, as evidenced by over seven years of real-world data (RWD).

"In about two years, we expect RWD on the second-generation BTK inhibitor, Brukinsa, will become available," Dr. Jeon said. "Based on results with 1st-generation BTK inhibitors, Brukinsa's data are expected to be very favorable. Although it has only been a short time, its satisfactory performance in the clinical setting is very encouraging."

Dr. Jeon has highlighted that a characteristic of 2nd-generation BTK inhibitors is their enhanced selectivity for BTK.

Typically, when a drug affects unintended targets, it can lead to adverse events such as cardiac hemorrhage, referred to as an off-target effect. 2nd-generation agents like Brukinsa have been designed to minimize these off-target effects.

Dr. Jeon said, "These agents have reduced the incidence of hematologic bleeding and cardiac issues seen in clinical trials to around 7–8%, less than half of previous rates, which is very encouraging," adding, "However, in real-world clinical practice, we focus more on managing gastrointestinal disturbances and onycholysis, side effects that can significantly impact patient adherence during long-term treatment."

"The criteria for BTK inhibitors are limiting…patient's life-long use of treatments must be considered"

Despite both 1st- and 2nd-generation BTK inhibitors being eligible for reimbursement, a significant limitation remains: if a patient fails on a 1st-generation BTK inhibitor, subsequent BTK inhibitor therapy is not reimbursable. Patients only have one opportunity for BTK inhibitor treatment when considering treatment sequencing.

Dr. Jeon had about five to six patients on 1st-generation BTK inhibitors that have been switched with Brukinsa.

Dr. Jeon explains that while patients already stabilized on 1st-generation therapy typically continue, new patients are generally started on Brukinsa whenever possible.

Yet, Dr. Jeon stressed that even though switching between 1st- and 2nd-generation therapies that both target the same molecule can be justifiable, it is critical to remember that these drugs are intended for lifelong use.

"Patients on 1st-generation BTK inhibitors often suffer from severe nausea and vomiting that disrupt their daily lives. In such cases, switching to Brukinsa, which has reduced off-target effects, has produced notably positive outcomes," Dr. Jeon said.

"It appears that the Health Insurance Review and Assessment Service (HIRA) considers switching unnecessary because the treatment offers a refined version of the same target," Dr. Jeon said. "Because forcing patients to endure painful side effects for a lifetime is like torture, 2nd-generation BTK inhibitors will represent an excellent alternative."

Finally, Dr. Jeon emphasized the urgent need to adopt CAR‑T therapies as a third-line treatment for MCL quickly.

"While CAR‑T therapy is already being implemented as third-line treatment overseas, it is not yet approved domestically, so they are available for use. However, the HIRA must propose an alternative so Korean patients could eventually receive treatment on par with those in other G20 countries," Dr. Jeon said.

"Approximately 85% of patients are filtered out during second-line BTK inhibitor treatment, leaving very few who progress to third-line treatments," Dr. Jeon said. "Although these treatments are high-cost, the financial burden is likely minimal due to the small patient population."