Description:
Minimal residual disease (MRD) detection has become standard of care in some hematologic malignancies such as acute lymphoblastic leukemia. While MRD has been studied in many different lymphoid and plasma cell malignancies, strategies based on techniques such as, flow cytometry, and detection of patient specific immunoglobulin gene sequence by molecular techniques such as allele-specific PCR have not been successful. Recent technical advances hold great promise in detecting residual disease and providing response assessment as well as prognostic information that may allow intervention to improve outcomes. In this joint session, the speakers will explore advances in using various forms of technology such as next generation sequencing in the context of circulating tumor DNA (ctDNA), mass spectrometry, high throughput biophysical measurements and molecular analysis of single cells to detect MRD. These technologies and application toward MRD detection will influence clinical trial design and improve outcomes for patients with lymphoma and plasmacytic neoplasms.

Dr. David Rossi will discuss the role cell-free circulating tumor DNA (ctDNA) in detecting residual disease. ctDNA in blood is an opportunity for comprehensive and minimally invasive lymphoma diagnostics that is not limited by sampling frequency, tumor accessibility, or the existence of clinically overt disease. Qualification of ctDNA is used for the identification of pre-treatment mutations associated with primary resistance to therapy and for the longitudinal non-invasive detection of acquired-resistance mutations under treatment. Quantification of ctDNA is used as a proxy of imaging for the measurement of tumor volume. It allows identifying residual disease after treatment also when the disease is in complete remission. Persistence of ctDNA detection during curative-intent therapy is proposed as dynamic prognostic marker for ultimate clinical outcome. Given the emerging role of the ctDNA, its implementation to detect genomic variants and residual disease is a priority in the roadmap of lymphoma research. Moving ctDNA applications from the bench to the bedside requires filling the uncertainties surrounding their clinical validity and, most importantly, clinical utility in the context of prospective clinical trials.

Dr. Katie Thoren will describe the use of mass spectrometry to detect M-proteins in multiple myeloma, identify the challenges of using this biomarker, and describe work that must be done for these techniques to be incorporated into clinical practice for tracking of low disease burden. Over the last several years, efforts have demonstrated that it is technically feasible to detect low levels of monoclonal proteins in peripheral blood using mass spectrometry. These methods are based on the fact that an M-protein has a specific amino acid sequence, and therefore, a particular mass. This mass can be tracked over time and can serve as a surrogate marker of the presence of clonal plasma cells.

Dr. Ash Alizadeh will discuss the spectrum of available technologies for lymphoma MRD detection and quantitation by next-generation sequencing, including the strengths and weaknesses of methods such as IgHTS, CAPP-Seq, PhasED-Seq, and related techniques.  He will separately discuss the role of ctDNA in several lymphoma subtypes using blood plasma, including for noninvasive lymphoma genotyping, disease classification, and risk assessment before therapy. Finally, he will discuss the use of ctDNA for early molecular response measurements as informative for adaptive clinical trial designs, for noninvasively detecting the emergence of resistance mechanisms, and for late MRD detection for early detection of progression.

Dr. Scott Manalis will discuss advances made towards monitoring and targeting MRD. Over the past decade, there have been significant advancements in microfluidic approaches for isolating rare cells and characterizing their molecular as well as biophysical properties. These approaches hold great promise for defining personalized vulnerabilities. His talk will focus on their prospects for monitoring as well as targeting MRD.