Detection of second primary lymphoma in late diffuse large B-cell lymphoma recurrences

Abstract: Approximately one-third of diffuse large B-cell lymphoma (DLBCL) patients relapse, who often require salvage chemotherapy followed by autologous stem cell transplantation. In most cases, the clonal relationship between the first diagnosis and subsequent relapse is not assessed, thereby missing the identification of second primary lymphoma. Here, the clonal relationship of 59 paired DLBCL diagnosis and recurrences was established by next-generation sequencing (NGS)-based detection of immunoglobulin gene rearrangements. In 50 cases with interpretable results, 43 DLBCL patients (86%) developed clonally related lymphoma and relapsed disease. In total, 100% of early recurrences (< 2 year), 80% of the recurrences with an interval between 2 and 5 years, and 73% of late recurrences (≥ 5 year) were clonally related. In contrast, 7 out of 50 patients (14%) showed distinct dominant clonotypes in primary DLBCL and its recurrences, suggesting the occurrence of second primary DLBCL, which all occurred at least 4 years after primary diagnosis. Moreover, 43% of clonally unrelated cases were Epstein-Barr virus-positive, while this was 3% in relapsed DLBCL. In conclusion, NGS-based clonality testing in late recurrences should be considered in routine diagnostics to distinguish relapse from second primary lymphoma, as this latter group of DLBCL patients may benefit from less intensified treatment strategies.