Most patients with low-grade lymphoma will achieve a clinical remission (CR) with standard chemoimmunotherapy. Yet, relapse from minimal residual disease (MRD), either as low-grade or high-grade disease, remains the leading cause of death. Several studies have provided consistent evidence showing the strong prognostic value of measurable MRD using flow cytometry, PCR, next-generation sequencing, or other approaches. While MRD includes the malignant cells that remain in a patient who achieves CR, not all MRD cells may have the functional capability to proliferate into relapse. We recently introduced a nomenclature to more precisely distinguish cells included within MRD. In this nomenclature, M-REC (Minimal-RElapsable Cancer) denotes fully transformed cells capable of driving a relapse; MN-REC (Minimal Non-RElapsable Cancer) denotes fully-transformed cells incapable of driving a relapse; and MRP (Minimal Residual Precursors) denotes residual cells that harbor somatic and/or phenotypic alterations but are not fully malignant, such as those causing a dysplastic “field-effect” in cancers like those of the bladder, head and neck, or esophagus. Studies that defined the genetic phylogeny of lymphoma using diagnostic, relapsed, and transformed B-cell lymphomas from the same patients have identified examples where MRPs repeatedly evolve into clinical lymphomas. This conflicts with the traditional model of cancer evolution, in which “relapses” result from M-RECs that persist after therapy. There are two immediate implications to this paradigm-shifting concept: 1) Many “relapses” are actually second lymphomas, and 2) defining and targeting the vulnerabilities of MRPs may be essential for improving lymphoma-free survival among patients who achieve a CR. It is important to note that the vulnerabilities of MRD may differ within the bone marrow, blood, lymph node, and other sites, so sampling of each is essential. To make this possible, we have advanced two strategies. First, we have established xenografts of human follicular lymphoma explants within immunocompromised mice that capture both malignant and nonmalignant cellular components, as well as predictable transformation to large-cell lymphoma in vivo. Second, we have initiated rapid autopsies of patients with disseminated lymphoma to obtain specimens from multiple organs and thereby define the heterogeneity of environmental niches that support the persistence of MRD.

Citation Format: Abner Louissaint, David Weinstock. Defining precursors in low-grade lymphomas that seed second lymphomas [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA40.