Relapse timing is associated with distinct evolutionary dynamics in DLBCL

Abstract

Diffuse large B-cell lymphoma (DLBCL) is cured in over 60% of patients, but outcomes are poor for patients with relapsed or refractory disease (rrDLBCL). Here, we performed whole genome/exome sequencing (WGS/WES) on tumors from 73 serially-biopsied patients with rrDLBCL. Based on the observation that outcomes to salvage therapy/autologous stem cell transplantation are related to time-to-relapse, we stratified patients into groups according to relapse timing to explore the relationship to genetic divergence and sensitivity to salvage immunochemotherapy. The degree of mutational divergence increased with time between biopsies, yet tumor pairs were mostly concordant for cell-of-origin, oncogene rearrangement status and genetics-based subgroup. In patients with highly divergent tumors, several genes acquired exclusive mutations independently in each tumor, which, along with concordance of genetics-based subgroups, suggests that the earliest mutations in a shared precursor cell constrain tumor evolution. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naive disease.

A mechanistic model of curative combination therapy explains lymphoma clinical trial results

“…Virtual trials were also used to calculated the statistical power of real trials, not based on an aspirational hazard ratio, but using a data-based prediction of hazard ratio, and correctly predicted that only RCHP-polatuzumab-vedotin and RCHOP-tucidinostat were likely to be significantly superior to RCHOP ( Figure 4D ). Our model does not reproduce the incidence of relapses later than 3 years, but recent genomic studies have found that ‘late relapses’ of DLBCL usually result from cancer precursor cells acquiring new mutations to develop into related yet de novo cases of DLBCL (55). Thus, the inability of our model to reproduce late relapses supports the theory that late relapses are effectively new and chemotherapy-naïve lymphomas.…”