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

Bladel, D.A.G. van; Stevens, W.B.C.; Kroeze, L.I.; Groen, R.A.L. de; Groot, F.A. de; Last-Kempkes, J.L.M. van der; Berendsen, M.R.; Rijntjes, J.; Luijks, J.A.C.W.; Bonzheim, I.; Spek, E. van der; Plattel, W.J.; Pruijt, J.F.M.; Jonge-Peeters, S.D.P.W.M. de; Velders, G.A.; Lensen, C.; Bladel, E.R. van; Fdermann, B.; Hoevenaars, B.M.; Pastorczak, A.; Bosch, J.V. ten; Vermaat, J.S.P.; Nooijen, P.T.G.A.; Hebeda, K.M.; Fend, F.; Diepstra, A.; Krieken, J.H.J.M. van; Groenen, P.J.T.A.; Brand, M. van den; Scheijen, B.

doi:doi:10.1182/bloodadvances.2023010412

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 underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 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...Show more 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 underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 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 patients with cHL for whom the clonal relationship could be established showed a second primary cHL. Clonal TCR gene rearrangements were identified in 14 of 125 samples (11%), and TCL-associated gene mutations were detected in 7 of 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/TCR 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.
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A significant proportion of classic Hodgkin lymphoma recurrences represents clonally unrelated second primary lymphoma