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Background: Recent genomic studies revealed enhancer of zeste homolog 2 (EZH2) gain‐of‐function mutations, representing novel therapeutic targets in follicular lymphoma (FL) in around one quarter of patients. However, these analyses relied on single‐site tissue biopsies and did not investigate the spatial heterogeneity and temporal dynamics of these alterations. Objectives: We aimed to perform a systematic analysis of EZH2 mutations using paired tissue (tumor biopsies [TB]) and liquid biopsies (LB) collected prior to treatment within the framework of a nationwide multicentric study. Methods: Pretreatment LB and TB samples were collected from 123 patients. Among these, 114 had paired TB and LB, with 39 patients characterized with paired diagnostic and relapse samples available. The EZH2 mutation status and allele burden were assessed using an in‐house‐designed, highly sensitive multiplex droplet digital PCR assay. Results: EZH2 mutation frequency was found to be 41.5% in the entire cohort. In patients with paired TB and LB samples, EZH2 mutations were identified in 37.8% of the patients with mutations exclusively found in 5.3% and 7.9% of TB and LB samples, respectively. EZH2 mutation status switch was documented in 35.9% of the patients with paired diagnostic and relapse samples. We also found that EZH2 wild‐type clones may infiltrate the bone marrow more frequently compared to the EZH2 mutant ones. Conclusion: The in‐depth spatio‐temporal analysis identified EZH2 mutations in a considerably higher proportion of patients than previously reported. This expands the subset of FL patients who most likely would benefit from EZH2 inhibitor therapy. [ABSTRACT FROM AUTHOR]

Recent advances in molecular technologies enable sensitive and quantitative assessment of circulating tumor DNA, offering a noninvasive disease monitoring tool for patients with malignant disorders. Here, we demonstrated on four follicular lymphoma cases that circulating tumor DNA based EZH2 mutation analysis performed by a highly sensitive droplet digital PCR method may be a valuable treatment monitoring approach in EZH2 mutant follicular lymphoma. EZH2 variant allele frequencies changed in parallel with the volume of metabolically active tumor sites observed on 18F-fluorodeoxyglucose positron emission tomography combined with computer tomography (PET-CT) scans. Variant allele frequencies of EZH2 mutations decreased or were eliminated rapidly upon successful treatment, with treatment failure being associated with elevated EZH2 variant allele frequencies. We also demonstrated spatial heterogeneity in a patient with two different EZH2 mutations in distinct anatomical sites, with both mutations simultaneously detected in the liquid biopsy specimen. In summary, circulating tumor DNA based EZH2 mutation analysis offers a rapid, real-time, radiation-free monitoring tool for sensitive detection of EZH2 mutations deriving from different anatomical sites in follicular lymphoma patients receiving immunochemotherapy. [ABSTRACT FROM AUTHOR]

We report the case of long-term persisting rheumatoid arthritis (RA), treated with CD20-CD19 CAR-T when it became associated with diffuse large B cell lymphoma (DLBCL), resulting in a sustained drug-free remission of the preceding RA, as well as of the subsequent DLBCL that formed the indication of the CAR-T therapy using zamtocabtagene autoleucel, with a 1-year follow-up. According to our best knowledge, this is the first published clinical case report of long-term persisting RA treated with CAR-T cell therapy., Competing Interests: Competing interests: DS, PT, PvH, GZ, SH, TO and SM are employees of Miltenyi Biomedicine GmbH. GN received speaker honoraria from Astra Zeneca, AbbVie, GSK, Lilly, Pfizer, MSD, Roche, Miltenyi, SOBI and Swixx., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)