With the widespread adoption of chemotherapy-free treatment regimens and breakthroughs in targeted therapies, chronic lymphocytic leukemia (CLL) treatment has entered a new era. At the 12th Lu Daopei Hematology Forum, Hematology Frontier invited Dr. Shenmiao Yang from Peking University People’s Hospital to provide an in-depth analysis of the current state of CLL treatment in China, discuss future research directions, and explore new chapters in the development of the field.

Hematology Frontier: Could you share the current state of CLL treatment? What challenges or unmet clinical needs do you believe exist in the treatment process?

Dr. Shenmiao Yang: CLL treatment has indeed entered a new era, where safe, chemotherapy-free regimens have become widely available and have demonstrated remarkable efficacy. Currently, several targeted treatment strategies have been approved both domestically and internationally, including long-term treatment with Bruton tyrosine kinase (BTK) inhibitors and short-term fixed-duration therapies (typically 12 months) combining BCL2 inhibitors with either CD20 monoclonal antibodies or BTK inhibitors. These three core strategies have provided patients with unprecedented clinical benefits and have greatly improved disease prognosis.

One of the most significant developments in CLL treatment this year is the final analysis of the RESONATE-2 study, which revealed that first-line CLL patients treated with ibrutinib monotherapy showed significant and sustained progression-free survival (PFS) and overall survival (OS) advantages over those treated with chlorambucil during a follow-up period of up to 10 years. Most patients achieved long-term stable disease control, highlighting the profound impact of this treatment regimen. Notably, at the 10-year mark, 27% of patients were still on ibrutinib with good tolerance, with a median treatment duration of 6.2 years.

Regarding quality of life, although survival has long been considered the primary indicator of treatment success for cancer patients, the overall survival of CLL patients has now become comparable to that of the general population. This shift signifies that CLL is gradually transitioning from a traditionally considered malignant disease to a manageable chronic condition. This transformation reflects advancements in medical technology and has brought substantial improvements in patients’ quality of life, heralding a new era in CLL treatment and management.

Hematology Frontier: CLL/SLL treatment is gradually shifting from the traditional “immunochemotherapy era” to the “targeted therapy era,” with chemotherapy-free regimens becoming a research hotspot. How do you view this trend’s impact on future CLL treatment goals?

Dr. Shenmiao Yang: With the rapid advancement of medical technology and the continuous expansion of treatment options, CLL patients’ treatment needs are undergoing profound changes. Initially, patients primarily focused on extending survival, aiming to achieve a lifespan similar to that of their peers. However, at this stage, patients’ expectations have expanded to include more comprehensive considerations, such as the impact of treatment regimens on quality of life, the potential risk of resistance, and the side effects and financial burden associated with long-term medication. As a result, short-term treatment strategies are becoming a new focus for both patients and the medical community, aiming to achieve disease stability while reducing the treatment duration and improving quality of life.

In the field of short-term therapy research, new treatment goals focus on achieving effective disease control and maintaining patient safety after treatment cessation. The core endpoints of such studies typically include progression-free survival (PFS) and the evaluation of minimal residual disease (MRD) status in the bone marrow and peripheral blood after treatment. Currently, whether MRD negativity can serve as a reliable surrogate endpoint for evaluating treatment efficacy is a widely discussed topic in the medical community. This discussion not only reflects the pursuit of treatment precision but also signals potential changes in future treatment evaluation systems.

Despite the emergence of new research endpoints, which may have a profound impact on the future treatment landscape, overall survival (OS) remains the gold standard for assessing treatment efficacy in clinical practice, and significant progress has already been made in this area. Building on this foundation, future research and development should increasingly focus on patients’ new needs and concerns—namely, improving quality of life while ensuring continued survival.

Therefore, we eagerly anticipate new developments in the field of short-term treatment, hoping these studies will provide more robust evidence that short-term treatment can effectively control the disease while also reducing the treatment burden and financial pressure on patients, thereby achieving more comprehensive and patient-centered treatment strategies.

Hematology Frontier: Could you share some of the research advancements in CLL treatment? What emerging treatment strategies are worth looking forward to?

Dr. Shenmiao Yang: In the comprehensive management and treatment of CLL, we are keenly anticipating a nationwide multi-center analysis of real-world data on long-term treatment with BTK inhibitors. This study is steadily advancing on the platform of the Chinese CLL Working Group, with strong support from Professor Jianyong Li at Jiangsu Province Hospital. This year, we were honored to submit two important papers at the American Society of Hematology (ASH) Annual Meeting, focusing on the long-term efficacy observations of ibrutinib and zanubrutinib in the real world. This work holds significant importance for the field of CLL treatment. Given the differences between domestic and international patient populations, data from Europe and the United States may not fully reflect the actual situation of Chinese patients. Therefore, domestic real-world data will provide valuable guidance for clinical decision-making in China. Moreover, the international success of zanubrutinib, especially its approval for CLL indications in Europe and the United States, underscores the guiding and leading role of long-term BTK inhibitor real-world data in global treatment strategies.

Meanwhile, both domestic and international studies have high hopes for short-term fixed-duration therapies, aiming to provide more benefits for patients. In China, although chemotherapy is still considered one of the important treatment options, exploring optimized combination regimens with new drugs to achieve stable efficacy has become a research hotspot. Our team is particularly focused on new combination strategies, such as different BTK inhibitors combined with BCL2 inhibitors ± CD20 monoclonal antibodies, in pursuit of deeper disease remission and long-term stability.

Additionally, emerging drugs such as BTK degraders have demonstrated unique treatment pathways by directly modulating the downstream BCR signaling pathway to degrade the BTK target protein, offering potential treatment hope for high-risk and dual-resistant patients. Another promising new target, the ROR1 ADC, has also shown positive progress abroad, and related domestic research is underway.

Considering the impaired T-cell function in CLL patients, CAR-T therapy faces significant challenges. In the ZUMA-8 study, the response rate of CD28 co-stimulatory domain CAR-T Axi-cel in CLL was suboptimal, while the TRANSCEND CLL 004 study showed some efficacy with the combination of Liso-cel and ibrutinib, but progression-free survival remains insufficient, prompting deep reflection on the future application of CAR-T in CLL.

Encouragingly, the progress in bispecific antibodies, such as CD19/4-1BBL, shows potential for deep remission in treating refractory aggressive lymphomas by enhancing T-cell function and combining with traditional therapies, drawing much attention to its results.

Finally, the active exploration of allogeneic CAR-T cell therapy and other areas by Chinese medical centers highlights the ongoing innovation and progress in CLL treatment in China. With the continuous emergence of new drugs and therapies and their scientific application by clinicians, the overall survival outcomes of CLL patients will continue to improve.

Expert Profile

Dr. Shenmiao Yang

• MD, Chief Physician, Director of the Hematology Institute, Peking University
• Key Social Positions: Member of the Lymphoma Group, Oncology Branch, Chinese Medical Association Member of the Lymphocyte Disease Group, Hematology Branch, Chinese Medical Association Member of the Chinese Society of Clinical Oncology (CSCO) Member of the China Anti-Lymphoma Alliance Member of the Chinese Chronic Lymphocytic Leukemia Working Group, Hematologic Oncology Committee, Chinese Anti-Cancer Association Head of the Beijing Chronic Lymphocytic Leukemia Working Group Member of the Malignant Lymphoma Working Committee, Hematology Branch, Chinese Geriatrics Society Member of the Lymphatic Hematology Committee, Chinese Society of Geriatric Oncology
• Main Areas of Expertise: Chronic lymphocytic leukemia, malignant lymphoma Invited by IARC/WHO to co-author the chapter on chronic lymphocytic leukemia epidemiology and monoclonal B lymphocytosis (CLL epidemiology and MBL) in the 5th edition of the WHO Classification of Haematolymphoid Tumours Involved in the development of domestic guidelines and expert consensus in related fields Leading related research and publishing related findings