Serum Soluble Interleukin-2 Level Determines Clinical Outcome In Patients with Follicular Lymphoma In Rituximab Era

Follicular Lymphoma (FL) is usually characterized by an indolent clinical course with a median overall survival (OS) ranging between 7 and 8 years before Rituximab (R) era. However, a minority of patients(pts) has rapidly progressive disease and in some cases histological transformation to high-grade lymphoma may occur. Recent large cohort studies suggested improved outcomes for pts treated in the last decade, First-line chemotherapy including R may produce excellent responses in pts with advanced FL, but most of pts invariably relapse even in R era. Early recognition of pts with poor prognosis is necessary to decide management and treatment of patients with FL. Some investigators have suggested that serum levels of cytokines and their soluble receptors might reflect tumor growth and host tumor responses. We have previously that soluble interleukin-2 receptor (sIL2-R) is a strong prognostic factor in aggressive lymphoma pts who received CHOP. In addition, we reported that sIL2R was a powerful tool which can discriminate favorable group from unfavorable group in diffuse large B-cell lymphoma pts who received R-CHOP. SIL-2R is a soluble form of interleukin-2 receptor (IL-2R). IL-2R is expressed on the cell membrane of lymphocytes and plays important roles in their activation and proliferation. The sIL-2Ra chain is induced and expressed only after mononuclear cell (T cell, B cell, monocyte, and natural killer cell) activation. Therefore, activated T and B cells have elevated levels of sIL-2R.

The aim of the present study is to assess the prognostic significance of serum sIL2-R in follicular lymphoma, especially in R era.

We enrolled total 94 pts with FL (including FL grade 1, 2, 3a). Twenty-three of 94 pts enrolled between Septenber1986 and November 2001 (group A: without R), and 71 between July 1999 and June 2009 (group B: with R). The group A pts received 6 cycles of CHOP and the group B pts six cycles of R-CHOP.

The median serum sIL2-R levels were 1320 (range 475– 8120) U/ml and 2407 (range 320–1690) U/ml in groups A and B, respectively. In group B pts who treated with R-CHOP, various poor prognostic features such as elevated LDH (p = 0.0001), Hb <12g/L (p=0.0009), advanced clinical stage (p = 0.0005) and involved nodal areas > 4 (p = 0.0385) were significantly associated with a high serum sIL2-R level. In group B, the median (range) serum sIL2-R levels of each FLIPI risk group were 651 (320–8120) U/ml in low risk group, 2677 (538– 5305) in intermediate risk group, 2935 (419–16900) in high risk group (p < 0.0001). The 10-years (yrs) OS rates for patients in group A with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 75.0% and 29.2%, respectively (p < 0.002). The 10-yrs PFS rates for pts in group A with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 22.9% and 15.2%, respectively (p < 0.05). The 5-yrs OS rates for pts with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 100 and 73.4%, respectively (p < 0.05) in group B. The 5-yrs PFS rates for pts in group B with sIL2-R < 2000 U/ml and ≥ 2000 U/ml were 80.3% and 44.3%, respectively (p < 0.001). Multivariate analysis in group B employing sIL2-R and some conventional prognostic factors demonstrated that sIL2-R for OS and for PFS was an only independent poor prognostic factor (OS; p=0.016, PFS p=0.0002, respetively). The results suggest that a high serum sIL2-R level predicts a poor prognosis in FL and may be a useful biomarker for selecting appropriate treatment.

Serum sIL2-R might be a powerful tool which can discriminate the prognosis for pts with FL. Long term follow up with many pts should be considered to confirm clinical usefulness of sIL2-R in pts with FL of R era.

No relevant conflicts of interest to declare.