Serum Soluble LR11 Can Predict High FLIPI-2 Score in Follicular Lymphoma.
Authors: Kawaguchi Takeharu , Ohwada Chikako , Shimizu Naomi , Takeuchi Masahiro , Sakaida Emiko , Takeda Yusuke , Sakai Shio , Tsukamoto Shokichi , Yamazaki Atsuko , Higashi Morihiro , Tamaru Jun-Ichi , Yokote Kotaro , Bujo Hideaki , Nakaseko Chiaki 
Published: October 2019

Abstract
Abstract 2673

Introduction:
Follicular Lymphoma International Prognostic Index 2 (FLIPI-2) is a widely accepted tool for risk assessment of follicular lymphoma (FL), which is based on age, hemoglobin level, presence of bone marrow (BM) invasion, tumor size, and b2-microgloblin levels. Although it is easy to evaluate in clinical practice, it is a combination of tumor burden and patient physical condition, and a simple and powerful biomarker reflecting the tumor burden and its character is still not established. LR11 (also called SorLA or SORL1) was identified and characterized as a regulator of uPAR function through complex formation with uPAR. We have identified that serum soluble LR11 (sLR11) levels are significantly elevated in patients with acute leukemia and B cell lymphomas, and are associated with tumor burden and BM invasion (Sakai et al 2012). We have also found that high sLR11 levels had a significant negative prognostic impact on progression-free survival (PFS) in FL. Therefore, we have retrospectively evaluated the clinical characteristics of sLR11 and its prognostic impact on FL, in a larger patient cohort.

Patients and Methods:
Sixty-one patients with FL treated at Chiba University Hospital and affiliated hospitals from 2002 to 2012 were evaluated. The majority of patients were treated by the R-CHOP regimen (rituximab 375 mg/m2 on day 1; cyclophosphamide, 750 mg/m2 on day 1; adriamycin, 50 mg/m2 on day 1; vincristine, 1.4 mg/m2 on day 1; and prednisolone, 100 mg/body on day 1–5). Serum sLR11 levels were measured by ELISA method. Patient laboratory data and treatment outcome were obtained retrospectively.

Results:
Serum sLR11 levels of patients with lymphoma were significantly increased (mean ± SD: 19.4 ± 17.1 ng/ml) compared with those of normal control subjects (8.8 ± 1.79 ng/ml, P<0.0001). Paired sample analysis at diagnosis and at remission showed significant reduction of sLR11 levels at disease remission (22.0 ± 23.9 ng/ml vs. 8.1 ± 3.0 ng/ml, P<0.0001). Multiple stepwise linear regression analysis showed that the serum sLR11 level at diagnosis was independently associated with BM invasion, lower Hb levels and elevated b2-microglobulin levels (r2= 0.48, BM invasion: P=0.0333, lower Hb levels: 0.0004, elevated b2-microglobulin levels: P=0.0289). Patients with “high” FLIPI-2 score showed significantly higher sLR11, compared to those with “intermediate” and “low” FLIPI-2 scores (29.2 ± 5.1 vs. 13.8 ± 7.7 ng/ml, p<0.0001). The receiver operating characteristic curve analysis showed that the cut off level of 15.4 ng/ml provided a maximum sensitivity (0.86) and specificity (0.82) for “high” FLIPI-2 score; the area under the curve was 0.84. At the median follow-up period of 15.7 months, the probability of 5-year PFS was significantly higher in patients with sLR11 >15.4 ng/ml at diagnosis compared with those with ≤15.4 ng/ml (Figure 1, 9.7 % vs 100 %, P<0.0001). Cox regression analysis showed that serum sLR11 levels >15.4 ng/ml at diagnosis was a significant prognostic factor for PFS (hazard ratio: 2.65 × 107, 95% CI: NA).

Conclusions:
Serum sLR11 levels in FL patients were associated with BM invasion, lower Hb levels and elevated b2-microglobulin, which are 3 of 5 variables in FLIPI-2. This suggests that serum sLR11 is a useful tool to predict “high” FLIPI-2 score, especially highlighting those with high tumor burden by simple serum evaluation and can be a promising biomarker in patients with FL.

Disclosures:
No relevant conflicts of interest to declare.