Mutational and copy number analysis at diagnosis and relapse of mantle cell lymphoma

Most patients diagnosed with mantle cell lymphoma (MCL) experience extended remissions following frontline chemoimmunotherapy, yet with extended follow-up, relapses seem nearly inevitable. This study aimed to define the genomic landscape of MCL at diagnosis and relapse and investigate the clonal evolutionary dynamics associated with progression of disease (POD). We conducted comprehensive genomic sequencing on 214 tumor specimens from 189 patients, including 144 treatment-naïve and 70 POD samples, with 25 patients providing longitudinal paired samples pre-treatment and at POD. Comparative analyses were performed on single nucleotide variants, insertions/deletions and copy number alterations to assess genomic differences between specimens from treatment-naïve and relapsed patients. Additionally, mutational signatures were evaluated in pre-treatment samples, stratified by time to progression (≤24 months vs. >24 months). One hundred patients who received standard frontline chemoimmunotherapy were included in the survival analysis. Genomic profiles of pre-treatment specimens from patients who ultimately relapsed were strikingly similar to those observed in POD, while distinctly different from profiles associated with prolonged remissions. This genomic 'stability' was further confirmed by analysis of 25 paired specimens, demonstrating a remarkable genomic concordance despite extended remission periods (median >3 years), without a clear pattern of acquired alterations. Our findings suggest that MCL relapse is predominantly driven by pre-existing malignant clones at diagnosis, rather than by new evolutionary events, underscoring the importance of early detection and eradication of resistant clones to improve long-term outcomes.