Introduction

Mantle cell lymphoma (MCL) is characterized by biological and clinical heterogeneity ranging from an indolent to highly aggressive lymphoma. Although prognosis is improving, prolonged impairment of quality-of-life due to treatments remain significant concerns, calling for biomarkers that could safely limit treatment for low-risk groups. In our multicenter open-label phase II trial ALTAMIRA (ASH abstract 747, 2024) treatment with time limited Acalabrutinib and rituximab (R) in elderly was associated with excellent outcomes in indolent patients. Disease characterization was based on clinical course, tumor tissue characteristics, or minimal residual disease negativity. However, easily accessible robust soluble biomarkers to accurately distinguish between high- and low-risk MCL patients upfront are generally lacking. Plasma proteins have emerged as promising biomarkers in various cancers. We therefore investigated whether plasma proteomics could identify novel soluble prognostic biomarkers, with the goal of enabling upfront treatment stratification and thus limit the risk of both under- and overtreatment in MCL.

Methods We conducted high-throughput plasma proteomic profiling using the Olink® Explore 1536 platform targeting 1460 proteins in the phase II ‘ALTAMIRA’ trial (n = 81, 75% men and 25% women), (≥60 years, median age 75) receiving rituximab and the Bruton Tyrosine Kinase inhibitor (BTKi) acalabrutinib 100mg BID as first-line therapy, and validated the finding in the population-based U-CAN cohort (n = 91), comprising all MCL patients included in the U-CAN biobank in Uppsala, Sweden 2010-2022, median age 70 (IQR 59-79) treated with time-limited chemoimmunotherapy, (the Nordic protocol for younger and R-Bendamustin for elderly). The primary outcome was absence of progression within 24 months of treatment initiation (POD24⁻). Differentially expressed proteins (DEPs) between indolent (POD24-) and aggressive (POD24+) cases were identified in both cohorts using the Olink® Statistical Analysis pipeline. Patients were stratified into high or low expression groups based on cohort-specific median Normalized Protein eXpression (NPX) levels. Survival outcomes were assessed using Kaplan-Meier and Cox proportional hazards models.

Results The protein ADAMTS8 consistently emerged as a marker of indolent disease among the top 10 DEPs in both cohorts, analyzed separately and combined, and ranked among the top two proteins elevated in indolent (POD24⁻) versus aggressive (POD24⁺) cases. High plasma levels of ADAMTS8 were significantly associated with improved 3-year overall survival (OS) in both cohorts, with an OS of 91.3% versus 68.3% in the ALTAMIRA cohort (p = 0.044) and 89.9% versus 56.4% in the U-CAN cohort (p = 0.0011). Median follow-up was 2 years in ALTAMIRA and 6.3 years in U-CAN, with long-term analysis in U-CAN confirming the survival benefit of high ADAMTS8 levels also over time (p = 0.009).

In the U-CAN cohort, high ADAMTS8 levels were associated with superior OS (HR 0.39, 95% CI: 0.19–0.81, p = 0.0116), and a similar trend was observed in the ALTAMIRA cohort (HR 0.29, 95% CI: 0.08–1.05, p = 0.0588). When the two cohorts were combined, high ADAMTS8 levels consistently predicted improved survival in unadjusted analysis (HR 0.35, 95% CI: 0.19–0.67, p = 0.0013), after adjusting for age (HR 0.43, 95% CI: 0.22–0.81, p = 0.0088) for MIPI score (HR 0.42, 95% CI: 0.22–0.8, p = 0.0081), and after multivariable adjustment for both age, morphology, and Ki67 (HR 0.45, 95% CI: 0.21–0.97, p = 0.041).

Conclusions ADAMTS8, a metalloproteinase with anti-angiogenic activity, has previously been proposed as a tumor suppressor in various solid cancers. This study is the first to demonstrate the favorable prognostic relevance of this putative tumor suppressor in MCL. Across two independent cohorts, a clinical trial with BTKi-based therapy and a population-based cohort with long-term follow-up and heterogeneous treatments, high plasma levels of ADAMTS8 were consistently associated with good prognosis. These findings identify ADAMTS8 as a promising, minimally invasive biomarker, with potential clinical utility for low-risk stratification in MCL and warrant further validation in prospective trials.

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2025
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