Immune-related protein signature in serum stratify relapsed mantle cell lymphoma patients based on risk

Abstract

Background Response to modern treatment strategies, which combine cytotoxic compounds with immune stimulatory agents and targeted treatment is highly variable among MCL patients. Thus, providing prognostic and predictive markers for risk adapted therapy is warranted and molecular information that can help in patient stratification is a necessity. In relapsed MCL, biopsies are rarely available and molecular information from tumor tissue is often lacking. Today, the main tool to access risk is the MCL international prognostic index (MIPI), which does not include detailed biological information of relevance for different treatment options. To enable continuous monitoring of patients, non-invasive companion diagnostic tools are needed which can further reduce cost and patient distress and enable efficient measurements of biological markers. Methods We have assessed if serum-based protein profiling can identify immune related proteins that stratify relapsed MCL patients based on risk. Overall, 371 scFv targeting 158 proteins were assessed using an antibody microarray platform. We profiled patients (n = 44) who had been treated within the MCL6-Philemon trial combining targeted and immune-modulatory treatment. Results The downstream processing led to the identification of the relapsed immune signature (RIS) consisting of 11 proteins with potential to stratify patients with long and short overall survival (OS). Moreover, in this population, MIPI alone failed to separate high, intermediate and low risk patients, but a combined index based on MIPI together with RIS, MIPIris, showed improved performance and significantly stratified all three risk groups based on OS. Conclusions Our results show that addition of biological parameters to previous prognostic indices improves patient stratification among patients treated with BTK inhibitor triplet combination, particularly, in the identification of an extreme high risk group.

Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

“…The antibody-target list can be found in Table S2 and the experimental protocol has been explained in detail in Lokhande et al 12 The generated dataset was quality controlled, followed by ComBat normalization (using surrogate variable analysis [SVA] package, www.r-project.org) to remove batch effects. 12…”

“…The experimental setup is identical to the published study and explained in detail in Lokhande et al, 2020. 12 For this cohort of patients (n = 44), the median follow-up time is around 5 years, with a median survival of 40.3 months and a median progression free survival of 17.6 months. Additionally, 25% of patients (n = 11) had ATM mutation and 52% (n = 23) of patients had TP53 aberrations (mutations or deletions; Figure 1).…”

“…12 Clinical and biological information was integrated and the MCL international index/relapsed immune signature (MIPI ris ) was developed and showed improved stratification of patients into three risk groups. 12 A separate previous study has also investigated the most common genetic alterations, including ATM and TP53 and their correlation to clinical outcome in MCL. 13 In this follow-up study, the IMMray™ protein microarray technology was used to investigate changes in serum proteome pre-and on-treatment.…”

“…11 Serum analysis on the pretreatment samples has been published, which led to the formation of a prognostic serum protein signature strengthening the established MIPI, and the development of the MIPI ris . 12 The current study is a follow-up of the previous serum analysis to study the effect of treatment on the serum proteome, and which biological information can be retrieved on response to therapy in the relapsed setting. The experimental setup is identical to the published study and explained in detail in Lokhande et al, 2020.…”

“…The trial includes immunomodulatory treatment with lenalidomide, BTKi ibrutinib and anti‐CD20 antibody rituximab. In a previous study, a prognostic signature (RIS; relapsed immune signature) based on 11 serum proteins correlated to overall survival was developed using the pre‐treatment samples 12 . Clinical and biological information was integrated and the MCL international index/relapsed immune signature (MIPI ris ) was developed and showed improved stratification of patients into three risk groups 12 .…”