During the 2024 American Society of Hematology Annual Meeting, Korea Biomedical Review gathered experts from Korea and the U.S. to discuss the transformative impact of CAR-T cell therapy and bispecific antibodies, focusing on challenges faced in the Korean healthcare system. The discussion revealed complex systemic barriers while exploring potential solutions for broader access to these revolutionary treatments. The first part of the discussion is between three Korean hematology leaders from the Korean Society of Hematology and Dr. Stephen J. Schuster from the University of Pennsylvania. -- Ed.

SAN DIEGO, Calif. – By Lee Han-soo/Korea Biomedical Review correspondent -- In a comprehensive roundtable discussion at the American Society of Hematology (ASH) 2024, Dr. Stephen J. Schuster from the University of Pennsylvania joined Korean hematology leaders from the Korean Society of Hematology (KSH) to address the evolving landscape of cellular therapies and immunotherapies in hematologic malignancies.

The conversation highlighted both the remarkable progress in treatment outcomes and the persistent challenges in ensuring patient access to these innovative therapies.

Transformative impact and economic considerations

Dr. Schuster emphasized the curative potential of these therapies, noting that "over the last 10 years we've developed immunotherapies that are actually curative.”

Schuster explained that the medical community now has 10 years of follow-up data for CAR T-cell therapy, which was pioneered at the University of Pennsylvania.

The economic aspects of these therapies sparked intense debate. Schuster emphasized that between 30 and 40 percent of patients achieve long-term disease-free survival with a single treatment, challenging traditional cost-effectiveness metrics.

He referenced a pivotal ICER analysis that demonstrated CAR-T's cost-effectiveness compared to ongoing palliative care costs and further advocated for price reductions, noting that he believes prices should come down because multiple CAR T-cell products are now on the market.

In the conversation, Schuster explained the practical implications of fixed healthcare budgets like Korea.

"If a country starts using its budget on numerous novel agents, it may struggle to provide routine care due to capital constraints from high-cost treatments," he said.

However, he then made an important counterargument about cost-effectiveness by discussing how treatments that appear expensive initially might be economically beneficial in the long run.

He explained that when considering patients with B-cell malignancies, there is a need to compare a single treatment that's potentially curative versus a succession of palliative treatments that ultimately end in death.

He emphasized that these palliative treatments also have significant costs.

Access challenges in Korea

Professor Kim Seok-jin, Chairman of KSH, detailed significant access barriers in Korea.

"Currently, Kymriah (ingredient: tisagenlecleucel) is the only available CAR-T therapy in Korea,” he said. “We cannot follow the global standard of care for relapsed-refractory diffuse large B cell lymphoma (R/R DLBCL) because Yescarta (ingredient: axicabtagene ciloleucel) and Breyanzi (ingredient: lisocabtagene maraleucel) are not available.”

As a result, Korea is purposely behind the global standard of care, he added.

Kim further elaborated on reimbursement challenges.

"Korea’s ambiguous reimbursement criteria sometimes require doctors to continue the same ineffective regimen until three or four cycles to define second-line failure,” he said. “This is ridiculous and delays patients' access to efficient treatment."

Responding to these concerns, Dr. Schuster proposed a solution, noting that the government could leverage the fact that there are three globally approved CAR T-cell products to negotiate reimbursement.

The discussion also highlighted the evolving role of bispecific antibodies in hematologic cancer treatment, with particular attention to their relationship with CAR-T therapy. While bispecific antibodies are technically available in Korea, they remain unreimbursed, creating a significant financial barrier for patients.

Kim emphasized their practical advantages over CAR-T therapy, including the convenience of outpatient administration, which could potentially reduce the overall burden on both healthcare systems and patients.

Schuster agreed with the need for both treatment options, explaining their complementary roles, and describing an emerging treatment paradigm where both modalities work together.

"These T cell-based immunotherapies are kind of a package," he explained. "For example, in aggressive B-cell lymphomas, we can now cure roughly a third, maybe 40 percent of patients who previously would have died with CAR-T.”

However, around 65 percent of patients still fail CAR-T treatment, and 20 to 30 percent of them respond to a bispecific, achieving durable remissions, he added.

The discussion revealed an even more innovative approach currently under investigation.

Schuster described ongoing studies using bispecific antibodies as a bridge to CAR-T therapy.

"These bispecifics are also going to allow CAR-T cell therapy to become more successful because they can control chemotherapy-refractory disease during the period of CAR-T cell manufacturing and help reduce the tumor so that the CAR-T is more effective,” he said.

Pediatric perspectives and early line treatment

Professor Kim Hye-ry, Public Relations Director of KSH, brought attention to challenges in pediatric leukemia treatment, particularly regarding Blincyto (ingredient: blinatumomab) access.

"While the drug is reimbursed, it's very limited. It's restricted to second-line use in adults and third-line in children,” she said. “Only after post-transplant relapse can you use Blincyto as a second-line treatment," she explained.

This limitation particularly affects specific patient populations.

"For Down syndrome patients, who often can't tolerate high-dose chemotherapy, Blincyto could play a crucial role,” she said. “If randomized studies show good results in this population, the question becomes whether we can use it as first-line therapy, but will insurance cover it?"

Highlighting recent developments, she added, "This year's ASH plenary session showed a randomized study in newly diagnosed standard-risk ALL patients that demonstrated better survival with two blocks of blinatumomab."

She expressed concern about the disconnect between emerging evidence and current reimbursement policies.

Schuster strongly supported earlier interventions and offered both clinical and economic perspectives.

"Drugs that work in patients who have failed everything work even better when you use them up front,” he said. “In the end, using Blincyto upfront may save money because fewer patients will fail and need it in the second and third line."

Schuster emphasized the role of public awareness in driving policy change.

Manufacturing challenges and market size impact

Professor Yoon Dok-hyun, the Research Support Director of KSH, highlighted the manufacturing challenges of CAR-T specific to smaller markets.

"We still have limited resources for manufacturing, and multinational pharmaceutical companies prioritize the supply to bigger markets,” he said.

This market-driven distribution creates a particular challenge for smaller nations seeking to leverage competition between multiple agents. While the presence of multiple approved products could theoretically help in price negotiations, the reality of limited manufacturing capacity and market prioritization often undermines this potential advantage.

Yoon added that while domestic development might offer a solution, regulatory hurdles remain significant.

"While developing our own CAR-T treatment may give us some room to utilize, the problem is they are for third-line diffuse large B-cell lymphoma, creating a gap in optimal care delivery,” he said.

Schuster responded positively to the local production plan.

"Manufacturing products in the country is not a bad idea because this is not rocket science,” he said. “The principles are pretty much worked out.”

When Yoon expressed concerns about the regulatory burden, Dr. Schuster acknowledged the challenge while advocating for a more dynamic regulatory approach.

"Regulations are in place to protect the public, and when they result in injury to people, they should be revised,” he said. “Regulation should evolve alongside technological advances, particularly as treatment paradigms shift.”

The American healthcare perspective

The discussion turned to the intricacies of the American healthcare system, where Schuster offered valuable insights into how different insurance mechanisms handle these costly treatments.

For Americans over 65, Medicare provides comprehensive coverage for CAR-T and bispecific treatments. The system extends similar coverage through Medicaid for low-income patients, ensuring access regardless of their financial situation.

The private insurance landscape, which covers more than half the population, presents a more complex picture.

Schuster revealed the obscure nature of healthcare financing in this sector, where actual costs remain hidden behind a veil of negotiated rates.

"That's a very obscure area of healthcare financing in the U.S. because physicians are never privy to it," he said. "The health systems negotiate deals with insurance companies and a company might say they're charging $100,000 for a product, but in reality, they only get paid $25,000."

Particularly noteworthy was Schuster's experience with insurance approvals for advanced therapies, which came as a shock to Korean physicians.

"I rarely get insurance denials," he stated, suggesting a high level of respect for clinical expertise in treatment decisions.

Korean physicians were starstruck as they regularly face strict reimbursement criteria and frequent denials, due to the ambiguous reimbursement criteria that often force doctors to continue ineffective treatments.

Schuster also explained that the system has developed innovative solutions for coverage gaps, particularly for oral medications not covered by Medicare.

“For example, there is a unique philanthropic system where pharmaceutical companies contribute to organizations like the Leukemia & Lymphoma Society, enabling patient access through grants,” he said.

Future directions and hope

Looking ahead, Schuster predicted significant advances within the next five years, particularly in universal T-cell development.

"We'll have strategies where we don't need products manufactured for individual patients," he said. "We'll be able to combine them with bispecifics, make them into CARs, and that eliminates the apheresis, processing, and much of the manufacturing costs."

The impact on patient outcomes appears promising. Schuster noted that CAR-T patients achieving complete remission showed normal life expectancy compared to age- and gender-matched populations.

"When patients go into remission, their immune systems reconstitute, and they're like normal people," he said.