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 Topics1. Genetic Heterogeneity in B-Cell LymphomasComplex genetic landscape of DLBCLImplications for treatment strategiesNeed for personalized approaches 2. Clinical Need for ctDNA in LymphomaWhy ctDNA is needed in aggressive lymphomas:Curative vs. non-curative treatment settingsLimitations of current PET imagingAdditional prognostic information beyond imagingRisk stratification capabilitiesPotential to avoid overtreatmentTherapy adaptation opportunities 3. Challenges in Lymphoma MRD AssessmentWhy lymphoma MRD is more complex than other hematologic malignancies:Differences from acute leukemias, CLL, and myelomaTechnical challenges specific to lymphoid tumorsLower circulating tumor burden compared to liquid tumors 4. ClonoSEQ TechnologyMechanism: Immunoglobulin sequencing approachAdvantages: Established platform with regulatory approvalDisadvantages: Limited sensitivity in peripheral blood, requires adequate tumor sample 5. CAPP-Seq TechnologyFull Name: Cancer Personalized Profiling by Deep SequencingInnovation: Developed ~10 years ago by Dr. Alizadeh's groupMechanism: Targeted sequencing of cancer-specific mutationsAdvantages: High sensitivity, personalized approach 6. PhasED-Seq TechnologyEvolution: Next-generation advancement of CAPP-SeqKey Improvements: Enhanced sensitivity and specificityTechnical Advances: Phased variant detection Clinical Data Highlights1. 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.70003. Korean data on prognostic utility of ctDNA: https://ashpublications.org/blood/article/142/Supplement%201/69/501573

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