Dynamic monitoring of circulating tumor DNA in non-Hodgkin lymphoma

Abstract

Response assessment in lymphoma relies on imaging scans that do not capture biologic processes at the molecular level. Monitoring circulating tumor DNA (ctDNA) with next-generation sequencing-based assays can detect recurrent disease prior to scans and "liquid biopsies" for somatic mutations address tumor heterogeneity, clonal evolution, and mechanisms of resistance to guide precision treatment. Preanalytic collection and processing procedures should be validated and standardized. We describe emerging applications of ctDNA monitoring including real-time analysis of tumor dynamics, preclinical disease detection, and precision-directed treatment paradigms.

Figure 1

Serial monitoring with circulating tumor DNA to guide precision medicine. Lymphomas are composed of multiple tumor clones and subclones that serially evolve over time, especially under the selective pressure of therapy. Liquid biopsies of ctDNA detect molecular features of resistant disease at the molecular level and can noninvasively genotype ctDNA throughout the disease course. Serial monitoring of ctDNA may be a powerful tool to address temporal heterogeneity of tumors, to detect clonal evolution, and to study mechanisms of treatment resistance. The timing and nature the dominant relapsing clone may guide precision treatment at relapse. As examples, patients who relapse with a myc rearrangement (green) might be offered targeted therapy with a BET inhibitor, whereas patients who relapse with a TP53 mutation (magenta) could be offered an MDM2 inhibitor.

Figure 2

Monitoring circulating tumor DNA enhances detection of relapse and defines molecular remission. The lead time offered by serial monitoring of ctDNA represents an opportunity for early intervention with minimal tumor burden. The clinical applications would differ when treating with curative intent (ie, aggressive lymphomas) or more extended duration of therapy (ie, indolent lymphomas). (A) Monitoring therapy for ctDNA for curative intent. The patient with no relapse (green) achieves a complete molecular remission and represents successful cure of lymphoma. The patient with late relapse (blue) initially achieves a complete molecular remission, but has ctDNA reappear before imaging, which creates a lead time for possible intervention. The patient with early relapse (red) has rising levels of ctDNA shortly after completion of therapy with a narrower lead time. The patient with primary refractory disease (brown) has persistence of minimal residual disease at the end of therapy that is undetectable by imaging. (B) Monitoring therapy with ctDNA for extended duration. Indolent lymphomas are frequently treated for extended durations with maintenance therapy designed to prolong duration of remission. Successful maintenance therapy (green) could be monitored with ctDNA and continued as long as disease remains undetectable. Patients who have the reappearance of ctDNA while receiving maintenance therapy (red) might be considered for alternative therapy before clinical effects. Patients who are not initially treated with maintenance therapy can be offered “delayed maintenance” at a time when disease is detectable by ctDNA, but not yet detectable by imaging scans.