In this episode of Blood Cancer Talks, hosts Eddie, Ashwin, and Raj welcome two distinguished experts to explore the cutting-edge field of circulating tumor DNA (ctDNA) in B-cell lymphomas. Dr. David Russler-Germain, a lymphoma clinician from Siteman Cancer Centre at Washington University in St. Louis, returns as a familiar voice to the podcast audience. Joining him is Dr. Ash Alizadeh, the Moghadam Family Professor of Medicine, Oncology, and Hematology at Stanford University and leader of the Cancer Genomics Program at Stanford Cancer Institute. Dr. Alizadeh has been instrumental in advancing our understanding of lymphomagenesis and lymphoma genetics over the past two decades, pioneering multiple ctDNA techniques that are revolutionizing cancer care. Together, they discuss the transformative potential of ctDNA technology in B-cell lymphomas, particularly DLBCL, covering everything from the technical evolution of biomarker detection to groundbreaking clinical data that may reshape how we monitor and treat these aggressive cancers.

Key Discussion Topics

1. Genetic Heterogeneity in B-Cell Lymphomas

Complex genetic landscape of DLBCL

Implications for treatment strategies

Need for personalized approaches

2. Clinical Need for ctDNA in Lymphoma

Why ctDNA is needed in aggressive lymphomas:

Curative vs. non-curative treatment settings

Limitations of current PET imaging

Additional prognostic information beyond imaging

Risk stratification capabilities

Potential to avoid overtreatment

Therapy adaptation opportunities

3. Challenges in Lymphoma MRD Assessment

Why lymphoma MRD is more complex than other hematologic malignancies:

Differences from acute leukemias, CLL, and myeloma

Technical challenges specific to lymphoid tumors

Lower circulating tumor burden compared to liquid tumors

4. ClonoSEQ Technology

Mechanism: Immunoglobulin sequencing approach

Advantages: Established platform with regulatory approval

Disadvantages: Limited sensitivity in peripheral blood, requires adequate tumor sample

5. CAPP-Seq Technology

Full Name: Cancer Personalized Profiling by Deep Sequencing

Innovation: Developed ~10 years ago by Dr. Alizadeh's group

Mechanism: Targeted sequencing of cancer-specific mutations

Advantages: High sensitivity, personalized approach

6. PhasED-Seq Technology

Evolution: Next-generation advancement of CAPP-Seq

Key Improvements: Enhanced sensitivity and specificity

Technical Advances: Phased variant detection

Clinical Data Highlights

1. Remission Assessment by ctDNA in LBCL on 5 prospective studies of frontline anthracycline-based chemo-immunotherapy: https://pubmed.ncbi.nlm.nih.gov/40802906/

2. Prospective validation of end of treatment ctDNA-MRD by PhasED-Seq in DLBCL patients from HOVON-902 clinical trial: https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.7000

3. Korean data on prognostic utility of ctDNA: https://ashpublications.org/blood/article/142/Supplement%201/69/501573