Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of non-Hodgkin's lymphoma, which accounts for the majority of lymphomas. In addition, the number of B-cell lymphoma patients in Korea is increasing due to the westernization of lifestyle and population aging.

DLBCL is characterized by rapid disease progression and frequent relapses. However, it can be cured if it responds well to treatment. In recent years, many new drugs with new modalities and mechanisms of action, including CAR-T and bispecific antibodies, have emerged, and patients' interest in treatment prognosis has also been increasing.

Against this backdrop, Korea Biomedical Review met with Professor Kim Seok-jin of the Department of Hematology and Oncology at Samsung Medical Center, who will take over as president of the Korean Society of Hematology in July, to listen to the latest views on DLBCL, the clinical implications of new drugs, and recommendations for improving access to treatment.

Question: The number of B-cell lymphoma patients in Korea has recently increased. What is the reason?

Answer: Except for some types, such as Hodgkin's lymphoma, which are more common in younger people, lymphoma is a disease that increases in frequency with age. Therefore, it is inevitable that the frequency will increase as we age. In particular, we see more B-cell lymphoma patients in our clinics than 10 years ago.

In addition to DLBCL, the number of patients with follicular lymphoma (FL), a low-grade, delayed-onset lymphoma considered less aggressive, has also increased dramatically. Follicular lymphoma is on a spectrum pathologically very similar to DLBCL, so vesicular lymphoma can come back and transform and become DLBCL.

Q: Please describe ‘R-CHOP,’ the current standard of care for DLBCL.

A: R-CHOP is a combination therapy consisting of cytotoxic anticancer drugs developed decades ago, such as cyclophosphamide (C), hydroxydaunorubicin (H, doxorubicin), Oncovin (O, vincristine), and prednisone (P), combined with rituximab (R), an immuno-oncology drug that targets CD20, which has been used in Korea for more than 20 years. It is still a standard of care today because the percentage of patients who benefit from this treatment is quite high.

However, about 40 percent of patients fail, so many clinical trials are underway to develop a more effective treatment than R-CHOP in first-line treatment. However, clinical trials that have added new agents to rituximab with R-CHOP as a control have continued to fail, meaning that R-CHOP is still a fairly effective treatment.

Q: What is the percentage of patients who do not respond to R-CHOP or relapse after treatment?

A: About 40 percent of patients relapse or become refractory after R-CHOP. In this case, we try a second-line treatment. If they respond, we can try a stem cell transplant. If the disease relapses after second-line treatment, the options include CAR-T therapy or participation in a clinical trial.

Q: What drugs are used for second-line treatment, and what is the treatment outcome at this stage?

A: Second-line regimens that are covered by health insurance in Korea include ESHAP (etoposide/methylprednisolone/cisplatin/cytarabine) and ICE (ifosfamide/carboplatin/etoposide).

These old cytotoxic agents theoretically allow you to use other cytotoxic agents that don't overlap with the CHOPs used in first-line treatment to kill cancer cells that have acquired resistance to conventional therapy. However, the results have been disappointing. They are more likely to cause side effects and are more cytotoxic. There is also the potential for opportunistic infections and sepsis if the patient is immunocompromised.

For every 100 people who fail first-line treatment, only about 30 patients respond to salvage treatment, which is currently covered by insurance in Korea and can proceed to autologous stem cell transplantation. This is because transplantation is difficult for older patients, and second-line treatments are often less effective in the aging population. Unfortunately, half of those 30 patients relapse. In conclusion, a conservative estimate of the percentage of patients cured in second-line treatment is 10-15 percent.

This makes second-line treatment for patients who have relapsed or failed first-line treatment the most vulnerable stage of the DLBCL treatment landscape in Korea. While CAR-T therapies are reimbursed for third-line treatment, there are no new reimbursed therapies for second-line treatment other than conventional cytotoxic chemotherapy, so patients are forced to either undergo conventional treatment or pay for very expensive drugs out of pocket. One option is participating in a clinical trial, which isn't easy. From the patient's perspective, second-line treatment is the largest unmet need.

Q: You said that the current second-line treatment of DLBCL is in a fragile state. Is it simply because of the low cure rate of existing treatment regimens?

A: It is a fact that everyone recognizes that there is a limit to the treatment with conventional cytotoxic anticancer drugs because patients suffer a lot when they proceed to second-line treatment, and the effectiveness is not satisfactory. In particular, (lymphoma treatment) is not ultimately about curing the disease but about taking care of people, and it is difficult for patients to play their role socially if they keep going to the hospital due to repeated relapses. It's also very hard on the caregivers.

For example, if you have a patient who was diagnosed with lymphoma in 2008 and survived for 10 years with multiple treatments and died in 2018, you might think that you did a good job because you helped a patient with stage 4 lymphoma survive for 10 years, but I don't think so.

I'm afraid I have to disagree because he had to spend most of those 10 years in treatment. Of course, the fact that he lived is important, but he lived in so much pain in terms of quality of life. That's why it's best to be diagnosed and treated and not relapse, and even if you do relapse, it's important to treat it quickly and effectively so that you can return to society as soon as possible and live the rest of your life in good health.

We need more effective treatments. Effective treatments need to be introduced quickly and covered by insurance so that people who have relapsed once don't relapse again and so that they don't have to go to a third or fourth treatment. This will also reduce medical costs for society.

Q: Various new drugs have recently been developed and licensed in Korea, and we wonder if the treatment environment will change.

A: Currently, Polivy (polatuzumab vedotin), rituximab + bendamustine, and other drugs are very expensive because they are not covered by benefits and must be administered out-of-pocket. Lenalidomide-based therapies are available as pre-application regimens but only from the third line. There are many options, but they are not readily available.

Q: Among the new drugs, Minjuvi (tafacitamab) was approved as a second-line treatment in Korea last year. We wonder how Korean patients will benefit from it.

A: Unlike rituximab, which targets CD20, Minjuvi targets CD19, and because it is a monoclonal antibody, it does not have severe side effects. The lack of side effects means that it can be used in older patients and can be treated on an outpatient basis. Clinical trial data has shown good results. In addition, lenalidomide, which is licensed as a combination therapy with Minjuvi, is a mainstay treatment for multiple myeloma and is already widely used.

While clinical trial data and real-world data can differ, and the true effectiveness of treatment will only be known when prescribed in a reimbursement setting, the fact that rituximab plus lenalidomide has shown better outcomes in some patients than traditional salvage cancer therapies indirectly suggests that Minjuvi plus lenalidomide may also show good results.

No plausible second-line therapies are available, so there is an urgent need to introduce agents with novel mechanisms of action, and rapid access is also important.

Q: Before Minjuvi, other CAR-T therapies were introduced in Korea and garnered much attention. The current reimbursed CAR-T therapies in Korea target CD19 just like Minjuvi, so there are concerns that the order in which the two drugs are prescribed will affect their effectiveness.

A: We do not believe that the use of Minjuvi will necessarily negatively impact the next generation of CAR-T therapies.

CAR-T therapies are also used in B-cell acute lymphoblastic leukemia (ALL) with CD19-targeted therapies with reimbursement. In DLBCL, the same agents are often used again after R-CHOP, albeit out-of-pocket, such as rituximab+lenalidomide, rituximab+GDP (gemcitabine/dexamethasone/cisplatin), and rituximab+ICE. Given this, the general idea is that exposure to a drug that targets the same target shouldn't have much effect as long as the target is still being expressed on the tumor cells.

More recently, CD20-targeting bispecific antibody drugs, such as Columvi (mosunetuzumab), Lunsumio (mosunetuzumab), and odronextamab have also been shown to be effective in patients who have already been exposed to CD20-targeting agents through R-CHOP. The practice of using agents with the same target but different mechanisms of action (MOAs) has been around for a long time. I don't think we need to be particularly concerned about CD19, and I don't think it will be as big a problem as it is with CD20.