‘DLBCL patients race against time with some dying while waiting’

The treatment landscape for diffuse large B-cell lymphoma (DLBCL) in Korea is entering a new turning point.

While CAR-T therapy, often called the “last weapon” for high-risk patients, has already entered the reimbursement system, the practical barrier of time required to initiate treatment remains significant.

On the other hand, the emergence of off-the-shelf bispecific antibodies, such as Epkinly (epcoritamab), has rapidly elevated “time” to a critical variable determining patient survival.

“It's not uncommon for patients to experience disease progression or death while waiting for CAR-T therapy,” Professor Choi Yoon-seok of the Department of Hematology at Korea University Anam Hospital said in a recent interview with Korea Biomedical Review. “In such cases, bispecific antibodies can be the only alternative.”

The reality of treatment just out of reach

DLBCL is one of the most common types of non-Hodgkin lymphoma, with 30-40 percent of patients relapsing or becoming refractory after first-line treatment. Only a portion of these patients reach the second-line standard treatment, autologous hematopoietic stem cell transplantation, and ultimately, only 10-15 percent of patients require third-line treatment.

For these patients, CAR-T (chimeric antigen receptor-T cell) therapy is often referred to as the “last weapon.” Indeed, the publication of long-term follow-up data spanning over 50 months has offered hope that long-term survival is possible for some patients.

However, CAR-T therapy requires a complex procedure: extracting T cells from the patient's blood, genetically reprogramming them, and then reinfusing them. This process alone takes at least four weeks, with the entire journey to actual administration taking 1.5 to 2 months.

“We've had cases at our hospital where patients had to wait a fortnight just for cell collection. However, DLBCL is such an aggressive disease that patients often can't endure that period, and the disease can progress explosively,” Professor Choi said.

Choi pointed out that even with the treatment right before their eyes, patients are faced with the reality of being unable to grasp it because they cannot overcome the “barrier of time.”

One patient Professor Choi was treating relapsed just three months after initial treatment. While preparing for an autologous transplant, the disease rapidly progressed again. The medical team decided on CAR-T therapy, but scheduling the screening tests and cell collection alone took over 10 days to complete. Learning that production would then require another four weeks left the patient and family frustrated.

“Ultimately, before treatment could begin, the patient's condition deteriorated rapidly. Medically, they were a suitable candidate for CAR-T therapy, but the situation effectively became a contraindication,” Choi said.

CAR-T's time barrier is surmounted by bispecific antibodies

Bispecific antibodies come to the fore precisely at this point. Unlike CAR-T therapies, they require no ex vivo manufacturing process, allowing for prescription and administration on the same day the patient arrives at the hospital.

“Bispecific antibodies like epcoritamab are ‘off-the-shelf’ drugs, meaning they can be used immediately. The biggest drawback of CAR-T therapy is time, and these antibodies offer an excellent alternative to address that issue,” Professor Choi explained.

Clinical trial data for bispecific antibodies are also positive. For Epkinly, even after three years of follow-up, the objective response rate (ORR) was 59 percent, the complete response rate (CRR) was 41 percent, and the median duration of complete response (mDOCR) was 36.1 months, numerically on par with CAR-T therapies.

In other words, while CAR-T therapies possess the weapon of long-term survival data, bispecific antibodies are emerging as a weapon that can save patients' lives in the clinical setting by leveraging their “immediate availability.”

Both show similar efficacy, and so the ultimate issue is ‘accessibility’

CAR-T therapies and bispecific antibodies have different mechanisms of action. CAR-T involves extracting the patient's T cells, genetically reprogramming them, and reinfusing them. Bispecific antibodies, however, directly link existing T cells within the body to cancer cells, triggering their attack. Ultimately, both therapies utilize immune cells to attack lymphoma.

"In terms of efficacy alone, the two treatments are almost identical, like shadows. The difference lies in the speed at which the patient is reached. Given that the immediate question is whether the patient can survive until tomorrow, the advantage of bispecific antibodies is clear," Professor Choi noted.

However, bispecific antibodies are not yet covered by the nation’s health insurance. The high drug price, costing tens of millions of won, is a major obstacle for patients to afford treatment out-of-pocket.

CAR-T therapies are covered, but patient access remains limited. Currently, only 14 institutions in Korea can provide CAR-T treatment.

“Operating a CAR-T center requires specialized personnel dedicated to processes like cell collection. However, labor and management costs are quite burdensome,” Professor Choi explained. “While cell collection infrastructure varies by hospital, most hospitals are already saturated due to space constraints, making it practically difficult to establish new facilities. Therefore, even large hospitals face limitations in adding collection equipment.”

That also explains why bispecific antibodies can serve as an excellent alternative to CAR-T therapies.

“Whether it's CAR-T or bispecific antibodies, the key question is whether patients can access them. If treatment opportunities themselves remain limited, as they are now, even the best drugs become meaningless,” Choi said.

Reimbursement policies must reflect unique characteristics of blood cancers

“DLBCL is grouped as a single disease, but it is actually highly heterogeneous. Therefore, more treatment options for DLBCL are always better,” Professor Choi said. “Even patients who have relapsed two or three times and were considered to have a poor prognosis can sometimes gain a new lease on life. Since there are always patients who respond to some treatment, giving up is never an option.”

Consequently, Professor Choi argued that the current reimbursement policy must be improved to better reflect the characteristics of blood cancers.

“Blood cancers require a different approach compared to general solid tumors. The government consistently demands overall survival (OS) data during new drug approval and reimbursement evaluations, but this is difficult to apply directly to blood cancers,” he pointed out.

For solid tumors, even a modest three-to-five months’ improvement in OS is accepted as reliable, meaningful data due to the limited efficacy of subsequent treatments. However, in blood cancers, patients often show some response to other rescue therapies even after third-line treatment. This creates a limitation where the pure OS improvement effect demonstrated by a specific new drug can be diluted by the impact of subsequent treatments, according to Professor Choi.

“If the current criteria are applied as is, more new drugs will fail to overcome the reimbursement barrier in the future,” he said.

For DLBCL patients, choosing a treatment is a race against time. CAR-T therapy offers hope for long-term survival. However, for patients who cannot wait, it remains a distant dream. In contrast, bispecific antibodies provide a new survival opportunity, leveraging their immediate availability.

“When patients cannot endure another day, time is life itself. This is precisely why new treatment options must enter the insurance coverage framework as quickly as possible,” Professor Choi said in conclusion.