Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

Abstract

• Elevated IL-2R, IL-1RA, and CXCL9 are associated with shorter event-free survival in newly diagnosed FL, treated with chemoimmunotherapy.• Increased serum IL-12 and IL-1RA is associated with shorter event-free survival in patients who were observed or treated with rituximab alone.Serum cytokines and chemokines may reflect tumor biology and host response in follicular lymphoma (FL). To determine whether the addition of these biological factors may further refine prognostication, 30 cytokines and chemokines were measured in pretreatment serum specimens from newly diagnosed FL patients (n 5 209) and from 400 matched controls. Cytokine levels were correlated with clinical outcome in patients who were observed or received single agent rituximab, or those who received chemotherapy.Correlations with outcome in chemotherapy treated patients were further examined in a separate cohort of 183 South West Oncology Group (SWOG) patients and all patients were then included in a meta-analysis. Six cytokines were associated with outcome in the Molecular Epidemiology Resource (MER) after adjusting for the FL international prognostic index. In patients who were observed or treated with rituximab alone, increased serum IL-12 and interleukin 1 receptor antagonist (IL-1RA) (P 5 .005 and .02) were associated with a shorter event-free survival. In patients receiving chemotherapy, hepatocyte growth factor, IL-8, IL-1RA, and CXCL9 (P 5 .015, .048, .004, and .0005) predicted a shorter EFS. When the MER chemotherapy treated patients and SWOG patients were combined in a meta-analysis, IL-2R, IL-1RA, and CXCL9 (P 5 .013, .042, and .0012) were associated with a poor EFS. (Blood. 2015;125(6):992-998) Introduction Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States.1 While classified as an indolent B-cell lymphoma, the clinical course exhibits a spectrum based on the FL international prognostic index (FLIPI) score with a remarkable tendency for patients to relapse.2 The overall survival rate of patients with FL was previous reported as 75% at 5 years, and ranged from 71% at 10 years for patients with a FLIPI score between 0 to 1, and 36% for those with a FLIPI score of .3. Currently, the median survival of all newly diagnosed patients is approximately 9 years. 3Although the overall survival appears to have improved with advances in chemoimmunotherapy, the median event free survival (EFS) remains around 2 years for patients with advanced disease. 4 As a prognostic score, the FLIPI has several limitations. It focuses on clinical factors and does not take into account biological factors such as the tumor microenvironment and the host response. Indeed, some studies have found better prognostication of the very high-risk group with the international prognostic index (IPI) rather than with the FLIPI. 5,6 The FLIPI may potentially be further improved, particularly in the high-risk categories, if biological data are added. Gene expression profiling studies on pretreatment specimens from patients with FL hav...

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

“…Finally, in the meta-analysis combining the MER chemotherapy cohort (n = 81) and the SWOG cohort (n = 183), elevated CXCL9 (HR = 1.96, 95% CI, 1.30-2.95; P = 0.0012), IL-2R (HR = 2.05, 95% CI, 1.16-3.61; P = 0.013), and IL-1RA (HR = 1.57, 95% CI, 1.02-2.42; P = 0.042) were significantly associated with shorter EFS. 102 Thus, the authors suggested that incorporation of these cytokines into future prognostic models should be considered.…”

“…However, these studies have typically been reported in a variety of lymphoma subtypes, and have often evaluated small numbers of patients and samples. Therefore, Mir et al 102 conducted a study using 30 cytokines and chemokines in a large cohort of patients to assess which serum cytokines and chemokines had predictive value independent of FLIPI, and thus, highlighted their potential for incorporation into a risk-stratified approach. 102 The study populations consisted of the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER) cohort, the SWOG cohort, and clinic-based controls from an ongoing case-control study of lymphoma patients who visited the Mayo Clinic Department of Medicine for a prescheduled general medical examination.…”

“…Furthermore, elevated serum levels of IL-1RA, CXCL9, and IL-2R were all associated with an inferior EFS (P = 0.042, 0.0012, and 0.013, respectively). 102 Moreover, the authors examined these 6 cytokines in the subset of 103 MER patients with less aggressive disease, and therefore, who were initially followed up with watchful waiting policies or treated with rituximab alone. They found that increased IL-12 (HR = 1.96, 95% CI, 1.23-3.15; P = 0.005) and IL-1RA (HR = 1.97, 95% CI, 1.11-3.48; P = 0.021) were significantly associated with a shorter EFS.…”

“…They found that increased IL-12 (HR = 1.96, 95% CI, 1.23-3.15; P = 0.005) and IL-1RA (HR = 1.97, 95% CI, 1.11-3.48; P = 0.021) were significantly associated with a shorter EFS. 102 They further examined these 6 cytokines in the subset of 81 MER patients with aggressive disease, and who therefore were initially treated with alkylator-or anthracycline-containing chemotherapy, such as R-CVP or R-CHOP. After adjusting for FLIPI and treatment (anthracycline, yes vs. no), CXCL9 (HR = 3.96, 95% CI, 1.82-8.59; P = 0.0005), IL-1RA (HR = 2.96, 95% CI, 1.40-6.26; P = 0.0045), hepatocyte growth factor (HR = 3.03, 95% CI, 1.24-7.41; P = 0.015), and IL-8 (HR = 3.19, 95% CI, 1.01-10.05; P = 0.048) were significantly associated with shorter survival.…”

“…102 The study populations consisted of the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER) cohort, the SWOG cohort, and clinic-based controls from an ongoing case-control study of lymphoma patients who visited the Mayo Clinic Department of Medicine for a prescheduled general medical examination. 102 The MER cohort included newly diagnosed, prospectively enrolled FL patients. The SWOG cohort was assembled from patients with available pretreatment serum from 3 SWOG clinical trials for newly diagnosed FL: S9800 (n = 27, a phase 2 trial of CHOP followed by rituximab), 103 S9911 (n = 29, CHOP followed by 131 I tositumomab), 104 and S0016 (n = 127, CHOP + rituximab vs. CHOP + 131 I tositumomab).…”