Background: Mantle cell lymphoma (MCL) is characterized by significant biological and clinical heterogeneity, necessitating the identification of prognostic biomarkers to guide its management. Circulating tumor DNA (ctDNA) has emerged as an innovative diagnostic and prognostic biomarker in various non-Hodgkin lymphoma subtypes and potentially extending its utility to MCL. The potential application value of ctDNA detecting in mantle cell lymphoma is unclear.

Methods: Thirty-eight MCL patients were enrolled in this study. Tissue, plasma, and bone marrow (BM) samples were obtained prior to initiation of first-line therapy for targeted sequencing, which included exons and selected introns of 475 genes associated with leukemia and lymphoma. Post-treatment plasma samples were also obtained from 17 of these patients for subsequent targeted sequencing analysis.

Results: In our cohort, the median age was 59 years (range, 37-76), with 10 individuals (26%) being over 65 years. According to the MCL International Prognostic Index (MIPI), 24 patients (63%) were classified as low risk. Clinical characteristics showed that 90% of patients had stage IV disease by the Ann Arbor staging system. Seven patients (18%) exhibited blastoid morphology, and 24 patients (63%) had a Ki-67 proliferation index of ≥30%. BM-flow cytometry (FCM), BM-NGS, and plasma-NGS tests were conducted on all 38 patients, with 33 also undergoing tissue NGS, yielding positive detection rates of 63.2%, 86.8%, 97.4%, and 100%, respectively. The targeted NGS sequencing for BM detection demonstrated 100% sensitivity compared to FCM. Nine patients with negative bone marrow FCM but NGS positive exhibited significantly lower pretreatment plasma ctDNA (Pre-ctDNA) levels and bone marrow mutation abundance. Plasma ctDNA identified mutations with high concordance to tissue results, achieving a 75% sensitivity rate. For the diagnosis-related gene CCND1 and the prognosis-related gene TP53, plasma ctDNA detection sensitivity was 94% and 100%, respectively. Analyses of plasma ctDNA quantification and mutation numbers indicated that higher pre-ctDNA levels and greater mutation numbers were significantly correlated with several adverse clinical factors, such as blastoid morphology, BM involvement, high MIPI risk, extranodal involvement at ≥3 sites, high Ki67 index, and the presence of B symptoms. Notably, higher Pre-ctDNA levels were observed in patients who did not achieve a complete response (CR) after treatment.

Gene and signaling pathway analyses of pre-ctDNA revealed that TP53 mutation, CARD11 mutation, and BCR signaling pathway mutation enrichment were significantly associated with a failure to achieve CR post-treatment. Further survival outcome analyses confirmed the negative impact of TP53 mutations and BCR signaling pathway mutation enrichment on long-term survival. Moreover, CDKN2A, ATM, FAT1, PI3K-AKT-mTOR pathway, and MAPK-ERK pathway were identified as unfavorable factors for overall survival (OS). Additionally, elevated pre-ctDNA levels and a higher number of mutations were significantly associated with poor OS (P<0.001 and P=0.005). Comparative analyses of 17 patients with post-treatment plasma samples showed that the log-fold change in ctDNA was significantly lower in patients in remission.. In contrast, two patients with elevated post-treatment plasma ctDNA levels demonstrated inferior progression-free survival (PFS) and OS

Conclusion:

Targeted NGS-based ctDNA testing represents a highly promising non-invasive approach, with pre-treatment plasma ctDNA exhibiting mutational and quantitative characteristics that significantly enhance the diagnosis and prognostic stratification of MCL. Elevated post-treatment plasma ctDNA levels in patients are indicative of a poor prognosis.

Disclosures

No relevant conflicts of interest to declare.

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2024
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