Evolutionary Dynamics Drive Behind Outcomes in Late DLBCL Relapses

Patients with diffuse large B-cell lymphoma (DLBCL) who relapse more than 2 years after their initial diagnosis have genetically distinct tumors compared with their initial disease, a new study has found.

The report, published in Journal of Clinical Oncology,¹ offers insights into why late-relapse patients tend to have better responses to second-line chemotherapy than early-relapse patients.

About 60% of people with DLBCL will be cured by first-line therapy, but those who experience relapse or whose cancers are refractory to therapy face more difficult odds, the study noted.

Patients who experience early relapse have particularly poor outcomes, but lead study investigator David W. Scott, MBChB, PhD, of the University of British Columbia, said in a press release² that new findings shed light on the need for different therapeutic approaches in patients with early relapses.

“With chemotherapy resistance baked into the tumor from the start, we require new tools for these patients,” he said. “New strategies, such as CAR [chimeric antigen receptor] T-cell therapy and bispecific antibodies, have emerged and the task is now to deliver these to our patients. Meanwhile, patients with late relapses have what we consider to be new lymphomas that can likely be cured with chemotherapy.”

To get to those findings, the team of investigators used a population-based cohort of 221 people with DLBCL whose cancers progressed or relapsed after frontline chemotherapy-based treatment and who were treated with second-line chemotherapy with the intention to perform autologous stem cell transplantation. The authors also examined serial biopsies from a subgroup of 129 patients who underwent molecular characterization; 73 of those patients had whole-genome or whole-exome sequencing performed.

In line with previous research, the authors found that the timing of a patient’s relapse affected that patient’s odds of successful second-line chemotherapy. Patients whose cancers progressed within 9 months of diagnosis (primary refractory) and those with early relapse (between 9 and 24 months after diagnosis) had inferior outcomes compared with those patients who relapsed more than 24 months after diagnosis.

When the investigators compared biopsies from the same patients, they got insights into why the timing of the relapse seems to matter.

“We compared the genetic make-up of pairs of tumors and found that in patients with late relapses, the relapsed tumor was very different from their first lymphoma tumor,” said co-author Laura K. Hilton, PhD, in the press release. “On the other hand, patients with earlier relapses showed greater similarities between their first and relapsed tumors.”²

Hilton said the latter finding suggests that resistance to treatment is already present in the tumors of early-relapse patients, even at the time of diagnosis.

The authors said these findings show that repeated biopsies and molecular analysis are important to understanding outcomes in patients with relapsed DLBCL and that these insights could help investigators design better clinical trials for targeted therapies and also better understand the outcomes of those trials.

They plan to continue their research by focusing on patients with early relapses and trying to identify which therapies are most effective in that patient group. They said they will also examine how common precursor cells contribute to the development of DLBCL and its response to therapy.

References

1. Hilton LK, Ngu HS, Collinge B, et al. Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma. J Clin Oncol. Published online June 15, 2023. doi:10.1200/JCO.23.00570

2. Study reveals cause of different outcomes for patients who experience relapse of diffuse large B-cell lymphoma. News release. UBC Faculty of Medicine. June 20, 2023. Accessed June 25, 2023. https://www.med.ubc.ca/news/study-reveals-cause-of-different-outcomes-for-patients-that-experience-relapse-of-diffuse-large-b-cell-lymphoma/