Soluble IL-2 Receptor α Is a More Sensitive Diagnostic Biomarker Than β2 Microglobulin and Predicts Survival in Follicular Lymphoma: Retrospective Analysis of 305 Cases
Authors: Yokohama Akihiko , Hashimoto Yoko , Hiroaki Shimizu , Saito Akio , Miyazawa Yuri , Iriujijima Hirono , Toyama Kotaro , Ishizaki Takuma , Mitsui Takeki , Koiso Hiromi , Takizawa Makiko , Saito Takayuki , Handa Hiroshi , Murayama Kayoko , Matsumoto Morio , Sawamura Morio , Murakami Hirokazu , Nojima Yoshihisa , Hirato Junko , Kojima Masaru , Tsukamoto Norifumi 
Published: November 2019

Abstract
Introduction: Soluble-form IL-2 receptor α (sIL-2Rα) has been identified as a significant prognostic biomarker in patients with non-Hodgkin’s lymphoma (NHL) treated using rituximab-containing regimens. However, the clinical significance of sIL-2R is not fully understood, especially in subtypes of NHL, such as follicular lymphoma (FL). In addition to sIL-2Rα, β2-microglobulin (B2M) has been used as a prognostic and diagnostic biomarker of FL. We compared the predictive and diagnostic abilities of sIL-2Rα and B2M for FL.
Patients and Methods: We analyzed 305 patients newly diagnosed with FL (Grade1-3a) between January 2001 and July 2012. Levels of sIL-2Rα and B2M were evaluated at diagnosis. The optimal cut-off values of sIL-2Rα and B2M were calculated from receiver operating characteristic (ROC) curves. Overall survival (OS) and progression-free survival (PFS, death from any cause, relapse and refractory disease) were analyzed using Kaplan-Meier methods and survival was compared using log-rank tests. To estimate the survival impact of several factors including sIL-2Rα, B2M, Hb<12g/dl, B symptoms, LDH, bone marrow involvement, bulky disease, extranodal disease and age, we performed multivariate analysis using the Cox proportional hazards model.
Results: Median age was 59 years (range: 28-86 years) and the male: female ratio was 1:1. Most (245/305) patients were treated with chemotherapy regimens. Rituximab was concomitantly administered to 227 of these patients (R-Chemo) and 52 of these patients received rituximab maintenance for 2 years. In the 305patients, clinical stage was I in 12.3%, II in 15.1%, III in 24.9%, and IV in 45.9% and the Follicular Lymphoma Prognostic Index was low in 35.7%, intermediate in 27.2% and high in 36.7%. The median follow-up period was 1,516 days (range: 7 - 4,776 days). The median sIL-2Rα value was 1,107.5 U/L (range: 127-20,800 U/L) and the median B2M value was 2.2 mg/L (range: 1.0-10.29). The 3-year OS of the entire population was 87.8% and the 3-year PFS was 65.1%. The percentage of patients whose sIL-2Rα or B2M level was higher than the upper normal limit (520 U/L for sIL-2Rα, 2.0 mg/L for B2M) at diagnosis was higher for sIL-2R (76.8%) than for B2M (54.2%) patients (p<0.0001), indicating that sIL2Rα is more sensitive diagnostic marker for FL than B2M. To estimate the predictive value of sIL-2Rα and B2M for survival, we determined the optimal cut-off levels of sIL-2Rα and B2M using ROC analysis. This analysis showed that sIL-2Rα and B2M values of 1,700 U/L and 2.2mg/Lrespectivelywere the most sensitive and specific values for prediction of a 3-year PFS. Using these values, patients were separated into two significantly different groups of sIL-2Rα values (>1,700 U/L and ≤1,700 (p<0.0001)) and of B2M values (>2.2 mg/L and ≤ 2.2 mg/L (p=0.0017)). Further, PFS differed significantly between patients with sIL-2Rα values of >520 U/L and ≤520 U/L, >1,000 U/L and ≤1,000 U/L ,and >2,000 U/L and ≤2,000 U/L (p=0.03, 0.0003 and <0.0001, respectively) and also between patients with B2M values of >2.0 mg/L and ≤2.0 mg/L, >2.5 mg/L and ≤2.5 mg/L, >3.0 mg/L and ≤3.0 mg/L (p=0.011, 0.0016 and 0.0184, respectively). Univariate analysis identified several reported prognostic factors, such as clinical stage3-4, B2M>2.2 mg/L, number of nodal site>5, bone marrow involvement, Hb<12 g/dl, performance status<2, number of extranodal site>1, longest diameter>6 cm (<0.0001, 0.002, 0.0002, 0.0204, 0.0345, 0.0089, 0.0004 and 0.0053, respectively) in addition to sIL-2Rα (p<0.0001). Cox multivariate analysis indicated sIL-2Rα as a significant prognostic factor (p=0.0361), in addition to several other factors (bone marrow involvement, number of extranodal site<2, number of nodal site>5). In the group treated with the R-chemo regimen, the 3-year OS was 86.9% and the 3-year PFS was 64.9%. Within this group, PFS significantly differed between the two groups of sIL-2Rα; >1,700 U/L and ≤1,700 (p<0.0001), and between two groups with different B2M values >2.2 mg/L and ≤ 2.2 mg/L (p=0.0056). Again, multivariate analysis showed that sIL-2Rα (>1,700 U/L), in addition to several other factors, was associated with poorer prognosis. Conclusion: This study showed that sIL-2Rα is a more sensitive diagnostic biomarker of FL than B2M. In terms of survival, sIL-2R is an important risk factor of FL, not only for all patients with FL, but also in the R-Chemo era.

Disclosures
Handa: Celgene: Research Funding; Yakult: Research Funding; Kirin: Research Funding; Chugai: Research Funding.