Comprehensive Genomic Analysis of Non-Relapsed and Late-Relapsed Mantle Cell Lymphoma Patients Compared to Refractory and Early-Relapsed Patients Treated By Standard Immunochemotherapy

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphomas (NHL), representing 3-10% of all NHL cases. The hallmark of MCL is translocation t(11;14)(q13;q32), leading to the overexpression of a crucial regulator of cell cycle progression cyclin D1 (CCND1). MCL is characterized by significant genomic heterogeneity and diverse clinical manifestations. Understanding the genomic landscape of MCL at the diagnosis onset holds considerable potential for developing predictive therapeutic strategies based on the mutational profile.

We focused on MCL patients at the disease onset, who were treated by standard immunochemotherapy represented by the alternation of R-CHOP-based regimens with high-dose cytarabine +/- platinum-based regimens, followed by rituximab maintenance and in transplant-eligible patients autologous stem cells transplantation. Patients were stratified according to their clinical post-therapeutic responses into 2 cohorts. Favorable cohort contained 30 patients who never relapsed or relapsed after ≥ 7 years post-therapy. Unfavorable cohort comprised 33 patients who relapsed in ≤ 2 years post-therapy or were considered to be relapsed/refractory. Genomic analysis using whole-exome sequencing (WES) was performed. We focused on mutational and copy-number variation (CNV) profiling.

WES revealed distinct mutational profiles in both cohorts of patients.

Favorable cohort contained a lower frequency of prognostically adverse mutations when compared with the unfavorable one. The most common mutation was identified in the CCND1 gene (28% of patients, 1 patient had 2 mutations), followed by mutations in IGLL5 and NSD2 genes (17%), and ATM, COL6A5, FAT3, KMT2D, MUC16, PCLO, SMARCA4 genes, each found in 10% of patients. Of note, mutations of the TP53 gene were observed only in 10% of patients within a favorable cohort, and in 39% of patients in the unfavorable one. Further mutational changes in the unfavorable cohort included mutations of ATM (33%, 3 patients had 2 mutations), CCND1 (18%), KMT2D, SP140 (15%), and CASP5, LRP1B, NOTCH2, and SMARCA4 (12%) genes.

CNV profiling revealed significant changes in both cohorts (q-value < 0.25 threshold was applied to control the false discovery rate).

Favorable cohort harbored amplifications of 3p, 3q, 8q, and 15q regions (q < 0.25). Amplifications of 8q and 15q chromosomal regions were exclusive only for the favorable cohort. Gains of PIK3CA and SOX2 genes were detected in 30% of patients within the favorable cohort, and 38% of patients in the unfavorable one. In addition, amplifications of BCL2 and MYC genes were unique only for the unfavorable cohort (19%, and 13% of patients, respectively). Deletions of genetic material were more prevalent in the unfavorable group and were represented by deletions of 1q, 6q, 8p, 9p, 9q, 13q, 15q, 17p, 21p, and 22p chromosomal arms (q < 0.25). Notably, deletions of CDKN2A/2B genes identified in 28% of patients were exclusive only for the unfavorable cohort. Other losses in the unfavorable group were represented by TNFAIP3 deletions (19%), SORBS3, TNFRSF10B deletions (13%), and ALDH1A1, ANXA1, and GNA14 deletions (9%). As for the favorable cohort, significant deletions of 6q, 8p, 13q, 16p, 17p, and 19q arms were identified (q < 0.25), comprising deletions of the MIR15A gene (20%), and ATM gene (17%). Only 7% of patients in the favorable group harbored deletions of the TP53 gene.

The unfavorable cohort demonstrated a higher frequency and broader spectrum of adverse genomic alterations.

Implementing genomic profiling in clinical assessment identifies patients with a high medical need for further sophisticated therapeutic approaches. Our results clearly identify a group of high-risk MCL patients, whose adverse genomic profile correlates with their clinical post-therapeutic outcome. These patients could benefit from integrating targeted therapy and innovative therapeutic approaches, such as CAR-T cell therapy, at the initial diagnosis. Clinical studies containing both modalities are currently under investigation (e.g., CARMAN study, NCT06482684).