Editor’s Note: From December 7–10, 2024, the 66th Annual Meeting of the American Society of Hematology (ASH) convened in San Diego, USA, bringing together global experts and scholars to discuss cutting-edge advancements in hematology. At this prestigious event, Dr. Wei Xu’s team from The First Affiliated Hospital of Nanjing Medical University presented their groundbreaking research titled Clinical Implications of CSF-Ctdna Positivity in Newly Diagnosed Diffuse Large B Cell Lymphoma in a Large Cohort. This study, selected for oral presentation (O576), not only deepens our understanding of CNS involvement in DLBCL but also offers innovative perspectives for clinical management and treatment strategies. Hematology Frontier invited Dr. Xu to share insights into the significance of CSF-ctDNA testing, its potential role in future DLBCL clinical practice, and its far-reaching impact on patient treatment strategies.

Key Highlights

• Superior Detection Rates: CSF-ctDNA testing demonstrated significant value in detecting CNS infiltration in DLBCL patients, with a positivity rate of approximately 25%, far exceeding the under 3% positivity rates of traditional methods, while establishing a prognostic evaluation system based on CSF-ctDNA.
• New Risk Assessment Model: The CNS-IPI index failed to fully reflect actual CNS involvement. A new system, CSFi-IPI, based on CSF-ctDNA, shows promise for more accurate risk assessment of CNS involvement.
• Challenges to Current Guidelines: High-dose MTX and intrathecal injection may be insufficient, as 37.5% of patients remained CSF-ctDNA positive post-treatment. A prospective study is ongoing to evaluate MTX combined with BTK inhibitors to enhance prophylactic efficacy.

Hematology Frontier: In your previous research, you validated the value of CSF-ctDNA in detecting CNS infiltration in DLBCL patients. In this large-scale cohort study, what new breakthroughs or findings did you uncover compared to prior studies? How do you foresee CSF-ctDNA testing influencing future clinical practice in DLBCL?

Dr. Wei Xu: At last year’s ASH conference, our team presented a study involving 100 retrospective cases and 24 prospective cases. Building on this foundation, we significantly expanded the prospective cohort to 222 DLBCL patients in the current study.

We conducted CSF-ctDNA testing for these patients and observed a positivity rate of approximately 25%. Compared to MRI, CT, or cytology—which have positivity rates below 3%—CSF-ctDNA testing represents a significant advancement in sensitivity and diagnostic capability. This study not only validates last year’s findings but also employs a more rigorous prospective design to confirm the reliability of the CSF-ctDNA-based prognostic evaluation system we developed for predicting outcomes in patients with CNS involvement.

Furthermore, we revalidated the CSF-ctDNA-based International Prognostic Index (CSFi-IPI) established in our prior retrospective study, reinforcing its reliability. Through a detailed analysis of mutation profiles, we found results consistent with last year’s findings, particularly the distinct mutational landscapes of DLBCL and primary CNS lymphoma. This provides key insights into the pathogenesis of DLBCL.

Additionally, we explored the mechanisms of CNS involvement at the single-cell RNA sequencing level. These investigations reveal the complex biology underlying CNS infiltration in DLBCL and open new avenues for future research and therapeutic development.

Hematology Frontier: Your study highlights that only a small percentage of patients with CSF-ctDNA positivity were diagnosed as CNSi-positive using traditional methods. Does this suggest that CSF-ctDNA testing can detect CNS infiltration earlier? What implications does this have for treatment strategies?

Dr. Wei Xu: Traditional diagnostic methods, such as imaging and CSF cytological analysis, have significant limitations, as demonstrated by their under 3% positivity rates in our cohort. To improve diagnostic sensitivity, we employed CSF-ctDNA testing, which showed a positivity rate of approximately 25%.

This important finding provides a strong scientific basis for implementing early interventions in these patients, potentially transforming treatment paradigms and improving patient outcomes.

Hematology Frontier: Your study suggests that traditional CNS prophylactic treatments may fail to clear CSF-ctDNA in some patients. Does this necessitate a re-evaluation of current CNS prophylactic strategies? What new treatment recommendations or insights do you propose?

Dr. Wei Xu: This study presents two major challenges to current guidelines:

1. CNS Risk Assessment: Existing guidelines rely on the CNS-IPI index for CNS risk evaluation. However, our findings indicate that CNS-IPI does not adequately reflect actual CNS involvement. To address this, we developed the CSFi-IPI, an innovative prognostic model based on CSF-ctDNA, which offers a more accurate risk assessment.
2. Prophylactic Treatments: Current guidelines recommend interventions such as intrathecal injections or high-dose methotrexate (MTX). However, our study found that while 62.5% of patients achieved effective CNS prophylaxis with these treatments, 37.5% remained CSF-ctDNA positive post-treatment.

To address these challenges, our team is conducting a prospective study focused on molecular subtyping of CSF-ctDNA. For patients with molecular subtypes such as MCD, N1, or BN2, we are exploring combination therapies that integrate BTK inhibitors with high-dose MTX to enhance CNS prophylaxis. By leveraging CSF-ctDNA genotyping, we aim to deliver personalized treatment strategies that improve prophylactic efficacy and patient prognoses.

The First Affiliated Hospital of Nanjing Medical University

• Title and Roles: Professor (Level 2), Chief Physician, Doctoral Supervisor, Postdoctoral Fellowship Supervisor Director, Geriatric Hematology Department Deputy Director, Hematology Department
• Academic and Professional Leadership: Vice Chair, Committee on Hematologic Oncology, Chinese Anti-Cancer Association (CACA) Chair, Lymphoma Subcommittee, CACA Chair, Hematology and Lymphoma Committee, Chinese Primary Health Care Association Vice Chair, Hematology and Lymphoma Committee, Chinese Association for Elderly Care Vice Chair, Hematology and Lymphoma Committee, Chinese Medical Education Association Standing Member, CSCO Chinese Anti-Lymphoma Alliance Standing Member, Hematology Committee, Chinese Women Physicians Association
• Regional and Provincial Contributions: Vice Chair, Hematology Branch, Jiangsu Medical Association Vice President, Hematology Division, Jiangsu Medical Doctor Association Chair, Lymphoma Committee, Jiangsu Research Hospital Association Chair, Jiangsu Anti-Lymphoma Alliance Vice Chair, Hematologic Oncology Committee, Jiangsu Anti-Cancer Association Chair, Nanjing Hematology Association

Dr. Xu is a prominent leader in hematology and lymphoma research, holding numerous academic and clinical leadership positions across national and provincial organizations. Her dedication to advancing lymphoma diagnosis, treatment, and research has earned her recognition as a key contributor to the field.