Significance of Soluble Interleukin-2 Receptor to Predict Prognosis and Support Decision-Making on Watchful Waiting for Stage II-IV Follicular Lymphoma Patients in the Rituximab Era
Authors: Muta Tsuyoshi , Okatani Takeshi , Itagaki Mitsuhiro , Suetsugu Yoshimasa , Noda Masaaki , Terasaki Tasuya , Kochi Yu , Jinnouchi Fumiaki , Mino Tatsuji , Imanaka Ryota , Kyo Kohei , Katayama Yuta , Katsutani Shinya , Iwato Koji , Asaoku Hideki 
Published: October 2019

Abstract
Background: Follicular lymphoma (FL) shows indolent clinical course and the optimal management strategy includes watchful waiting (WW). To define prognostic models for WW in clinical practice, we focused on serum soluble interleukin-2 receptor (sIL-2R) in the era of rituximab (R).
Methods: To evaluate risk stratification of patients with FL, we employed the current retrospective study. The data and follow-up information of patients were collected from three medical centers. The diagnosis of FL is made by the WHO criteria. Eligible patients were aged 18-90 years, previously untreated, and diagnosed between 2004 and 2016. WW was considered as an initial approach for patients with asymptomatic, no organ damage by lymphoma, or lacking bulky disease. Progression-free survival from diagnosis (PFS1) was defined as the time from diagnosis to disease progression requiring therapy in WW, first progression after frontline active therapy, or death from any cause. Progression free survival after active therapy (PFSA) was defined as the time from anti-lymphoma therapy to progression or death, and PFS2 was defines as the time from diagnosis to secondary progression or death from any cause. This study was approved by the independent ethics committee or institutional review board at participating institutions.
Results: Total 291 patients with newly diagnosed FL with stage II-IV and with grade 1-3a were included. Of these, 12.7% of patients were older than 75 years, 45% were men, 62.5% had stage IV disease, 18.9% were elevated LDH, 16.7% were beta 2-microglobulin (B2m) beyond 3 mg/L, 7.2% were grade3a, and 32.0% were FLIPI-high. The serum levels of B2m and sIL-2R were measured in each center, and the examination rates were 88.6% and 100%, respectively. In a simple linear regression, statistic correlation between serum B2m and sIL-2R of individual patients were confirmed with R-squared of 0.4 and P-value of <0.001. The sIL-2R of 1000 IU/mL was correlated with B2m of nearly 1.2 mg/L. The proportion of patients with sIL-2R ≤500, >500 ≤1000, and >1000 were 18.9%, 26.8%, and 54.3%, respectively. Total 89 patients (30.6%) had a first-line management strategy of WW, and during the median follow-up of 6.9 years, 52 patients required active therapy consisted of R-CHOP like (100%). The other 202 patients received frontline active therapy, included R-CHOP like (82.7%), R-CVP (12.9%), R-bendamustine (1%), or R-monotherapy (3.4%), and only 5 patients received R-maintenance. With a median follow-up of 5.5 years, there were 8 deaths in WW and 22 in frontline active therapy, demonstrating no difference in overall survival (P = 0.3). Based on multivariate analysis, factors associated with PFS1 are sIL-2R of ≤500, >500 ≤1000 IU/mL, and >1000 IU/mL (HR, 1.34; 95% CI 1.03-1.74) and stage IV (HR 1.71, 95% CI 1.11-2.63), while gender, age >75 years, B2m >3.0 mg/L, elevated LDH, and histological grade were not significant. When divided into three groups using sIL-2R, 6-year PFS1 were 74.2%, 51.4%, and 40.3%, respectively (P <0.001) in the entire patients, and were 65.2%, 41.4%, and 20.7%, respectively (P <0.001) among patients with WW. Overall, PFS1 of patients with WW was not so favorable as those with frontline active therapy (HR 1.43; 95% CI 1.01-2.02, P = 0.043), but PFS2 was equivalent (HR 1.57; 95% CI 0.76-3.27, P = 0.22). Among patients with sIL-2R ≤1000 IU/L, 6-year PFS1 was equally favorable in patients with WW compared to frontline active therapy (51.9% vs. 70.4%, P = 0.06; Figure 1), and 6-year PFSA was also equally favorable (80.6% vs. 67.7%, P = 0.75). On the contrary, among patients with sIL-2R >1000 IU/L, WW was associated with inferior PFS1 (HR 3.00; 95% CI 1.48-3.89; Figure 1) and PFS2 (HR 2.87; 95% CI 1.25-6.60) compared with frontline active therapy. The rate of histological transformation (HT) was similar: 5 in WW vs. 4 in frontline active therapy (P = 0.1). Median time to HT from diagnosis was 6.0 years (1.2-7.0) in WW, which was quite longer compared to 1.3 years (0.3-1.8) in frontline active therapy (P = 0.01). Secondary myeloid malignancies had developed in 4 patients at median 3.6 years (2.5-6.2) after frontline active therapy.
Conclusion: For FL patients, the usefulness of sIL-2R is demonstrated for predicting intervals from starting WW until therapy requirements. In addition to general guidelines, the variable of sIL-2R ≤1000 IU/L at diagnosis was the simple indicator to recommend WW to postpone active therapy without impairing prognosis.

Disclosures
No relevant conflicts of interest to declare.