Editor's Note: Lymphoma is a common malignant disease of the lymphatic system that poses a significant threat to public health. China faces a rapidly increasing burden of lymphatic tumors. The GBD 2019 study shows that China accounts for 10.8% of the world's new cases of Hodgkin lymphoma and 9.8% of the deaths, as well as 20.1% of the new cases and 17.4% of the deaths from non-Hodgkin lymphoma. Therefore, improving lymphoma diagnosis and treatment levels is a critical challenge in China. To gain a deeper understanding of the current status and progress of lymphoma diagnosis and treatment in China, Hematology Frontier interviewed Dr. Dr. Lugui Qiu, Director of the Lymphoma Diagnosis and Treatment Center at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences , for an in-depth analysis of this topic.

Hematology Frontier: The Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences , is a leading institution in the treatment and research of hematological diseases in China. As the head of the Lymphoma Diagnosis and Treatment Center, could you share some of the important research progress your center has made in the field of lymphoma in recent years?

Dr. Lugui Qiu : Over the past two decades, our team has been committed to the precision diagnosis and treatment of lymphoma, as well as related laboratory biological research. In summary, we have made some progress in several areas:

1. Establishing a Precision-Based Lymphoma Diagnosis and Treatment System: We have developed a precision diagnosis and treatment system for lymphoma that combines static prognosis stratification with dynamic prognosis stratification based on treatment efficacy assessments (including minimal residual disease monitoring). This approach allows for timely adjustments to treatment strategies, leading to better outcomes for more lymphoma patients, including improved long-term survival and cure rates. Leveraging this system, our center has established a lymphoma-specific database, which includes nearly all lymphoma patients treated at our center. The database was updated through the end of 2022 and contains over 8,000 cases, yielding the following results: Indolent B-cell Lymphoma: Cases of indolent B-cell lymphoma account for over 50% of the lymphoma cases (more than 4,000 cases). In a follow-up study we published in 2016 (n=1600), we found that the median overall survival (mOS) for indolent lymphoma exceeded 10 years, with a median progression-free survival (mPFS) of nearly 4 years, which is comparable to international survival data from the same period. Since 2016, with the broader application of molecular targeted drugs, the expected mOS for patients with chronic lymphocytic leukemia (CLL) and Waldenström macroglobulinemia (WM) has reached 15 years. Aggressive Lymphoma: In the field of aggressive lymphoma, our team recently published a cohort study involving more than 300 patients with diffuse large B-cell lymphoma (DLBCL), showing a 5-year PFS of over 75%, indicating that more than three-quarters of DLBCL patients could achieve a cure through our lymphoma diagnosis and treatment system. Among high-risk DLBCL patients, the 5-year PFS exceeded 60%, while the cure rate for low-risk patients surpassed 80%, placing our treatment outcomes among the best in the world. Mantle Cell Lymphoma (MCL): We have treated over 250 cases of MCL, with 5-year PFS and OS exceeding 40% and 60% respectively in younger patients. However, elderly MCL patients who cannot receive systemic treatment have a significantly poorer prognosis. Through cohort analysis, we identified two main factors affecting survival improvement in younger MCL patients: (1) The application of new drugs, including rituximab and BTK inhibitors, and (2) The implementation of induction chemotherapy (based on high-dose cytarabine) combined with autologous stem cell transplantation (ASCT). For elderly MCL patients, survival improvement mainly depends on whether they can receive new drug treatments.
2. Advancements in ASCT Combined with CAR-T Therapy for DLBCL: Our center has also made significant progress in applying ASCT combined with CAR-T therapy for DLBCL. After myeloablative conditioning, autologous hematopoietic stem cells are infused, followed by the infusion of CAR-T cells within 2-3 days. Our center primarily uses the anti-CD19 CAR-T (CNCT 19) developed by Professor Jianxiang Wang’s team, which has been approved for the treatment of relapsed/refractory adult acute lymphoblastic leukemia (R/R-ALL) and has also been submitted for approval for use in relapsed/refractory DLBCL (R/R-DLBCL). Led by Professor Dehui Zou, a study published in The Journal for Immunotherapy of Cancer reported on 30 R/R-DLBCL patients treated with CAR-T combined with ASCT, showing an ORR of 92% and a CR rate of 70% after a median follow-up of over 40 months. This efficacy is far superior to that achieved with CAR-T or ASCT alone, with an expected 2-year PFS exceeding 70%, offering hope for remission and cure in R/R-DLBCL.
3. Investigator-Initiated Trials (IIT): Considering China’s unique circumstances, including patients’ poor long-term medication adherence, we have explored a “limited cycle treatment model” using BTK inhibitors combined with immunochemotherapy for indolent B-cell lymphomas. Several related IITs are ongoing, including an early study on CLL using the “sandwich regimen,” where immunochemotherapy is first used to reduce tumor burden, followed by 3 months of ibrutinib treatment, then alternating immunochemotherapy and ibrutinib courses. Treatment is discontinued if MRD-negative CR is achieved. For patients with TP53 deletion or mutation, ibrutinib maintenance is continued for 6 months to 1 year before stopping. This study has completed enrollment, with a median follow-up of over 4 years, showing an ORR of 92% and a CR rate of 68%. Notably, among 47 patients who completed treatment, ORR was nearly 100%, and over one-third of patients discontinued treatment. After more than a year of follow-up post-treatment, only one patient died from a COVID-19 infection, while others remained in CR. This indicates that the limited cycle treatment model combining immunochemotherapy with BTK inhibitors is highly suitable for China’s conditions and achieves remarkable efficacy and survival outcomes.

The advantage of immunochemotherapy lies in its ability to be discontinued, making it a limited cycle treatment, and combining it with BTK inhibitors further reduces the chemotherapy cycles, thereby lowering chemotherapy-related toxicity. This reminds us not to discard previously proven effective treatments just because new drugs emerge. This limited cycle treatment model enhances patient compliance and saves significant medical resources. Currently, this model is being explored in WM, CLL, and marginal zone lymphoma (MZL).

1. Clinical Trials of New Drugs: Our center has led multiple clinical studies of new drugs in the lymphoma field, resulting in the approval and commercialization of several new drugs in China, including: Biosimilar CD20 Antibody, Darbrolib: Approved based on successful results from phase I and III head-to-head studies led by our center, significantly replacing imported CD20 monoclonal antibody original drugs. Original Class 1 New Drug: A Novel PI3Kδ Inhibitor, Lymphoritis: I led the phase I and pivotal registration phase II trials for this drug, which was approved in China in November 2022 for the treatment of relapsed/refractory follicular lymphoma (R/R-FL) in adults. We also explored expanded indications with an Ib phase study for relapsed/refractory peripheral T-cell lymphoma (R/R-PTCL), involving 40 R/R-PTCL patients. The ORR for Lymphoritis exceeded 60%, with over one-third achieving CR, a median PFS of over a year, and median OS not yet reached. We believe Lymphoritis is an outstanding PI3Kδ inhibitor with high target selectivity and safety superior to any other approved PI3K inhibitor, many of which have safety concerns and have been withdrawn or carry black-box warnings. PI3Kδ Inhibitor + Chemotherapy: After Lymphoritis’s approval, we conducted a clinical study combining PI3Kδ inhibitors with chemotherapy, enrolling over 30 patients. The results so far are very encouraging, with reliable safety and no treatment-related deaths. We hope to develop a new treatment regimen combining PI3Kδ inhibitors with chemotherapy to improve the efficacy of relapsed/refractory lymphomas. CNCT 19 (anti-CD19 CAR-T) Developed by Dr. Jianxiang Wang’s Team: This therapy has shown remarkable efficacy and has been submitted for approval for the treatment of relapsed/refractory DLBCL (R/R-DLBCL). Zanubrutinib (Highly Selective BTK Inhibitor): Our center led the pivotal registration phase II clinical study of zanubrutinib for treating relapsed/refractory WM.
2. Biological Research: Our center has achieved some results in biological research on diseases such as CLL, MCL, and WM. For example, in CLL biology, we have identified distinct biological characteristics of Chinese CLL patients compared to those in Western countries: The IGHV gene mutation rate in Chinese patients is significantly higher, reaching two-thirds. The gene mutation spectrum also differs, with higher mutation rates of KMT2D and MYD88 and lower NOTCH1 mutation rates in Chinese CLL patients. Chinese CLL patients tend to have better biological prognoses, which may explain why their survival outcomes are comparable to those in Western countries despite later disease staging and poorer access to new drugs.

In the field of MCL, we have used multi-omics analysis to classify MCL into molecular subtypes and study clonal evolution. This research was featured on the cover of The Journal of Clinical Investigation (February 2022 issue). We identified four molecular subtypes: C1, C2, C3, and C4, each with distinct characteristics:

1. C1 subtype MCL patients have an excellent prognosis, with stable clones and no complex cytogenetic abnormalities, and the B-cell receptor (BCR) signaling pathway is significantly upregulated, making them well-suited for BTK inhibitor treatment.
2. C2 and C3 subtype MCL patients have moderate prognoses, mostly classical MCL, with similar outcomes under immunochemotherapy. However, their drug choices should differ in targeted therapy; C2 subtype patients have upregulated NF-kB and DNA repair signaling pathways, making them more suited for treatment with NF-kB inhibitors like bortezomib and lenalidomide. In contrast, C3 subtype patients have downregulated NF-kB and BCR signaling pathways, making them less sensitive to BTK inhibitors and better candidates for other inhibitors like PI3K or BCL-2 inhibitors.
3. C4 subtype MCL patients often have MYC pathway activation, overexpression of proliferation-related genes, TP53 mutations or deletions, and del(9p). These patients have a poor prognosis, are typically refractory to chemotherapy, and are insensitive to single-target therapies, so multi-target combination treatments are recommended. After achieving remission, allogeneic stem cell transplantation (allo-HSCT) is also advised.

This MCL molecular classification system proposed by our center has significant prognostic and therapeutic guidance value in clinical practice. Building on this, we further studied MCL clonal evolution, finding that most MCL patients experience varying degrees of clonal evolution upon relapse, with some showing significant changes, such as multiple complex cytogenetic abnormalities, resulting in a very poor prognosis. Lastly, in proteomics research, we found that combining proteomics, DNA genomics, and RNA abnormalities can enable more precise prognosis stratification for MCL, though this is still under investigation. Our center is relatively leading in this field globally.

In the field of WM, our center has conducted extensive research. By the end of 2022, a cohort study involving 450 WM patients observed survival differences under different treatment regimens, showing that survival continues to improve as access to new drugs increases.

We were also the first to propose the concept of “oligoclonal Waldenström macroglobulinemia” and explored its biological characteristics. Notably, we were the first to discover the expression of T-cell genes and proteins, such as CD3 and CD8, in the clonal B cells of WM. This finding was first published in 2019, and subsequent single-cell sequencing confirmed this phenomenon, identifying CD138(+), CD3(+), and CD8(+) subpopulations, which warrant further investigation. Biological research revealed that CD19/CD3/CD8 positive cells might have stronger clonal formation abilities, potentially contributing to WM pathogenesis. This finding is currently under further functional research and has been corroborated by other scholars both domestically and internationally.

In summary, by establishing a comprehensive and precise diagnosis and treatment system, our center has significantly improved the cure and long-term survival rates of lymphoma patients. We have led clinical trials for new drugs, increasing the availability of new lymphoma treatments in China. Finally, we have made important progress in biological research on lymphoma, particularly in CLL, MCL, and WM, with some advancements being internationally leading. These research efforts and advancements have contributed significantly to the field of lymphoma diagnosis and treatment in China.

Dr. Lugui Qiu

• Director of the Lymphoma Diagnosis and Treatment Center, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences
• Chief Physician, Doctoral Supervisor
• Chief Scientist, Gao Bo Myeloma Research Institute
• Director, Tianjin Cord Blood Hematopoietic Stem Cell Bank
• Recipient of the State Council Government Special Allowance, National Health Commission Outstanding Contribution Award for Young and Middle-Aged Experts
• Member, International Myeloma Society (IMS)
• Member, Expert Committee, International Myeloma Working Group (IMWG)
• Editorial Board Member, Blood Advances
• Honorary Chair, Hematological Oncology Committee, Chinese Anti-Cancer Association
• Deputy Chair, Lymphoma Expert Committee, Chinese Society of Clinical Oncology
• Deputy Chair, Hematology Institution Branch, China Hospital Association
• Deputy Chair, Hematology Professional Committee, Chinese Medical Education Association
• Vice President, Sixth Council of Tianjin Anti-Cancer Association
• Editorial Board Member of six core journals, including Chinese Journal of Hematology
• Completed over 30 national key projects, including the National Science and Technology Support Program and National Natural Science Foundation key projects
• Published nearly 500 papers, including over 150 SCI papers; authored five monographs; holds five national invention patents
• Awarded two first prizes for provincial and ministerial-level achievements