The Impact of Genetic Subtypes of Diffuse Large B-Cell Lymphoma for Outcome Prediction and Interpretation of FDG-PET treatment Response Monitoring

Abstract Next-generation sequencing (NGS)-based genetic subtyping and interim- and end-of-treatment 18 fluorodeoxyglucose-positron emission tomography (i/eot-PET) have high potential for upfront and on-treatment risk assessment to guide personalized treatment of diffuse large B-cell lymphoma (DLBCL-NOS). We performed NGS genetic subtyping according to the Dana Farber Cancer Institute (DFCI) and LymphGen using biopsy samples in a combined cohort of DLBCL-NOS patients of the HOVON84 (n=208) and PETAL (n=204) clinical trials together with NGS data of 304 DFCI study samples. For all uniformly R-CHOP treated patients (n=592), the DFCI-C5, -C2, LymphGen-MCD and -A53 genetic subtypes showed significantly worse outcome independent of IPI. Adverse prognostic value of i/eot-PET positive status was confirmed for all subtypes. However, DFCI-C2 patients showed slow response to reach negative eot-PET status of only 67% versus rapid response of 81-88% for all other subtypes, implicating frequent primary refractory disease. Outcome for i/eot-PET negative patients remained significantly worse for DFCI-C5 in HOVON-84 (negative predictive value 81% versus 88% for C1-C4), which trend validated independently in both PETAL and SAKK38-07 trial patients, indicating high rates of relapse despite reaching complete metabolic response. These results show the added value of genetic subtyping for prognostic stratification and for the value of i/eot-PET for treatment response monitoring.