Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma

Author:

Hilton Laura K.12ORCID,Ngu Henry S.1ORCID,Collinge Brett13ORCID,Dreval Kostiantyn24,Ben-Neriah Susana1ORCID,Rushton Christopher K.2,Wong Jasper C.H.1,Cruz Manuela2,Roth Andrew5,Boyle Merrill1,Meissner Barbara1,Slack Graham W.13,Farinha Pedro13ORCID,Craig Jeffrey W.13ORCID,Gerrie Alina S.16ORCID,Freeman Ciara L.7,Villa Diego16ORCID,Rodrigo Judith A.89,Song Kevin89,Crump Michael10,Shepherd Lois1112ORCID,Hay Annette E.1112ORCID,Kuruvilla John10,Savage Kerry J.16ORCID,Kridel Robert10ORCID,Karsan Aly4ORCID,Marra Marco A.1413ORCID,Sehn Laurie H.16ORCID,Steidl Christian13ORCID,Morin Ryan D.124ORCID,Scott David W.16ORCID

Affiliation:

1. Centre for Lymphoid Cancer, BC Cancer, Vancouver, British Columbia, Canada

2. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada

3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

4. Canada's Michael Smith Genome Sciences Centre, BC Cancer Research Institute, Vancouver, British Columbia, Canada

5. Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, British Columbia, Canada

6. Division of Medical Oncology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

7. Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

8. Department of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

9. Leukemia/BMT Program of BC, Vancouver General Hospital, Vancouver, British Columbia, Canada

10. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

11. Canadian Cancer Trials Group, Queens University, Kingston, Ontario, Canada

12. Department of Medicine, Queens University, Kingston, Ontario, Canada

13. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

Abstract

PURPOSE Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. PATIENTS AND METHODS Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. RESULTS Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. CONCLUSION These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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