A significant proportion of classic Hodgkin lymphoma recurrences represents clonally unrelated second primary lymphoma

Diede Ag van Bladel, Wendy B C Stevens, Leonie I Kroeze, Ruben Al de Groen, Fleur A de Groot, Jessica Lm van der Last-Kempkes, Madeleine R Berendsen, Jos Rijntjes, Jeroen A C W Luijks, Irina Bonzheim, Ellen van der Spek, Wouter J Plattel, Johannes Pruijt, Susan Dpwm de Jonge-Peeters, Gerjo A Velders, Chantal Lensen, Esther R van Bladel, Birgit Federmann, Brigiet Hoevenaars, Agata PastorczakJutte van der Werff Ten Bosch, Joost S P Vermaat, Peet Nooijen, Konnie M Hebeda, Falko Fend, Arjan Diepstra, J Han Jm van Krieken, Patricia J T A Groenen, Michiel van den Brand, Blanca Scheijen

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Despite high cure rates in classic Hodgkin lymphoma (cHL), relapses are observed. Whether relapsed cHL represents second primary lymphoma or an underlying T-cell lymphoma (TCL) mimicking cHL is under-investigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (IG) and T-cell receptor (TR) rearrangements was performed in paired cHL diagnosis and recurrences of 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal IG rearrangements were detected by next-generation sequencing (NGS) in 69/120 (58%) diagnosis and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24/34 patients (71%). Clonally unrelated cHL was observed in 10/34 patients (29%) as determined by IG-NGS clonality assessment, and confirmed by the identification of predominantly mutually exclusive gene mutations in the paired cHL samples. In recurrences of >2 years, ~60% of cHL patients for which the clonal relationship could be established showed a second primary cHL. Clonal TR gene rearrangements were identified in 14/125 samples (11%), and TCL-associated gene mutations were detected in 7/14 samples. Retrospective pathology review with integration of the molecular findings were consistent with an underlying TCL in 5 patients aged >50 years. This study shows that cHL recurrences, especially after 2 years, sometimes represent a new primary cHL or TCL mimicking cHL, as uncovered by NGS-based IG/TR clonality testing and gene mutation analysis. Given the significant therapeutic consequences, molecular testing of a presumed relapse in cHL is crucial for subsequent appropriate treatment strategies adapted to the specific lymphoma presentation.

Original languageEnglish
Pages (from-to)5911-5924
Number of pages14
JournalBlood Advances
Issue number19
Early online date8-Aug-2023
Publication statusPublished - 29-Sept-2023

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