Pre-treatment serum IL-10 predicts the risk of secondary central nervous system involvement in patients with diffuse large B-cell lymphoma
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common, aggressive non-Hodgkin lymphoma accounting for 30–40% of cases worldwide [1]. The treatment outcome of patients with DLBCL has significantly improved since the introduction of rituximab in combination with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) [2], [3]. However, more than 30% of patients still experience relapse even after they achieve a complete response, and they ultimately have a poor prognosis [4], [5]. In particular, central nervous system (CNS) relapse carries poor outcomes in most patients; however, secondary CNS involvement is a relatively uncommon event occurring in around 5% of DLBCL patients [6], [7], [8]. Thus, appropriate CNS prophylaxis should be performed in highly selected patients. However, the identification of high-risk patients for CNS relapse still remains controversial. In the past, clinical risk models, such as the International Prognostic Index (IPI), and the involvement of certain sites, such as the paranasal sinus, testis, and retroperitoneal lymph nodes, were considered to indicate a higher risk of secondary CNS involvement [9], [10], [11], [12]. Currently, the CNS-IPI model combining five IPI factors with kidney or adrenal gland involvement is recommended as a risk model to help identify high-risk patients for CNS relapse [13]. However, clinical risk models have limitations because their parameters may not reflect all aspects of biological aggressiveness. As our understanding of the molecular pathogenesis of DLBCL has advanced, high-grade B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6, also known as double- or triple-hit lymphoma, has been considered a risk factor for CNS relapse [14], [15]. However, this may not be sufficient for predicting CNS relapse because these patients only account for about 5% of DLBCL, and not all patients have CNS relapse.
Cytokines and chemokines are involved in normal homeostasis, such as inflammation and wound healing; however, chemokines are also involved in tumor cell migration, contributing to tumor cell proliferation and survival [16], [17]. In addition, their role in tumor growth and metastasis has been demonstrated in various malignancies, including lymphomas [18]. For instance, interleukin-6 and -10 (IL-6, IL-10) in cerebrospinal fluid (CSF) reportedly have a role in the diagnosis of primary CNS lymphoma [19]. Considering that IL-6 and IL-10 are major cytokines related with the JAK/STAT pathway, which plays a role in tumor growth of DLBCL, the serum levels of IL-6 and IL-10 may represent the likelihood of secondary CNS involvement and risk of CNS relapse. Indeed, elevated serum levels of IL-10 were closely associated with JAK2 activation and MYC and Bcl-2 expression in DLBCL [20]. Chemokine (C-C motif) ligand 3 (CCL3), a pro-inflammatory chemokine produced by many cells such as macrophages and lymphocytes, is also known to be produced by lymphoma cells, and CCL3 can attract accessory cells to the tissue microenvironment in response to B cell receptor (BCR) signaling, which is an important pathway in DLBCL [21], [22]. Constitutive elevation of serum chemokine (C-C motif) ligand 5 (CCL5) was associated with immune evasion of lymphoma cell-lines [23]. TNF-α (tumor necrosis factor-α) is an important pro-inflammatory cytokine that plays a central role in immune responses and acts as an inducer of IL-10 secretion in vitro [24]. The elevated plasma level of this cytokine adversely impacted outcomes of Hodgkin’s lymphoma patients [25]. However, data about the impact of these cytokines on the secondary CNS involvement of DLBCL are lacking. Therefore, we analyzed the association of pretreatment serum cytokines and chemokines with the occurrence of CNS relapse in DLBCL patients who had serum samples available for study to analyze their role in predicting the occurrence of CNS relapse.
Section snippets
Patients
We retrospectively analyzed the clinical data of DLBCL patients (n = 313) who were enrolled in a prospective cohort study between September 2008 and December 2011 (NCT#00822731). All patients were newly diagnosed as having DLBCL according to the 2008 World Health Organization classification [26]. Patients who had archived serum samples available for analysis were analyzed, and primary CNS lymphoma was excluded. We analyzed the recorded data of the cohort study including information at the time
Patient characteristics & clinical outcomes
The median age of 313 patients was 56 years (range, 16–86 years), and 177 patients (57%) were men. Most patients were in good performance status, with 261 patients (83%) in ECOG PS 0–1 and 52 (17%) in ECOG PS 2–4. Overall, 159 patients (51%) had localized disease with Ann Arbor stage I/II, whereas 154 patients (49%) had stage III/IV; 107 patients (34%) showed involvement of ≥2 extranodal sites, and increased serum LDH was detected in 169 patients (45%). Accordingly, 144 (46%), 59 (19%), 51
Discussion
Secondary CNS involvement has long remained a concerning issue in the management of DLBCL patients because CNS relapse carries nearly universally poor outcomes [28], [29]. Furthermore, once patients show CNS relapse or progression during or after treatment, systemic disease progression usually occurs following CNS involvement. Considering that CNS involvement is usually an exclusion criterion for participation in clinical trials of novel agents, it is of critical importance to identify patients
CRediT authorship contribution statement
Jun Ho Yi: Conceptualization, Formal analysis, Data curation, Writing - original draft. Yoon Sang Eun: Conceptualization, Investigation, Data curation. Kyung Ju Ryu: Conceptualization, Investigation. Young Hyeh Ko: Conceptualization. Won Seog Kim: Conceptualization, Resources, Writing - review & editing, Supervision. Seok Jin Kim: Conceptualization, Methodology, Resources, Writing - review & editing, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We thank all our colleagues for participating in the research and express our gratitude to the 20-20 project of Samsung Medical Center and the National Research Foundation of Korea (NRF-2017R1A2B4005136).
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Both authors contributed equally to this article.