Increased C-Reactive Protein Level Is Associated with Poor Prognosis in Patients with Follicular Lymphoma Treated with Rituximab-Containing Regimens

Introduction:

C-reactive protein (CRP) is a useful inflammatory marker in clinical practice. It is a prognostic factor in several types of tumors, including diffuse large B cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma, nasal type. However, in follicular lymphoma (FL), its prognostic significance is controversial. We retrospectively evaluated clinical, pathological, and laboratory factors, including serum CRP levels, and analyzed the correlation with clinical outcomes in newly diagnosed patients with FL treated with rituximab-containing regimens.

Methods:

We analyzed 82 newly diagnosed patients with FL treated with rituximab-containing regimens for initial therapy at our hospital from 2003 to 2017. The median age of the patients at diagnosis was 63.5 years, and the median follow-up period was 1813 days (range, 231-5295 days). Histological grades revealed grade 1-2 (n = 57) and grade 3a (n = 17) and some patients' whose histological grades could not be evaluated due to needle biopsy (n = 8). All patients were treated with rituximab-containing regimens: rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) (n = 71), rituximab alone (n = 9), and rituximab plus bendamustine (n = 2). We further analyzed the relationships between clinical outcome [overall response rate (ORR), complete response (CR), progression-free survival (PFS), and overall survival (OS)] and clinical data, including sex, age (≥65 years), performance status (≥2), FLIPI (≥HI), laboratory parameters [white blood cell count (≥5000/µl), lactate dehydrogenase (LDH; elevated or normal), soluble interleukin-2 receptor (elevated or normal), and CRP (elevated or normal)], and histopathological findings, including histological grade, immunohistochemical expression of Ki-67 (≥ 30% of cells), and bcl-6 (≥ 30% of cells) at initial diagnosis.

Results:

ORR was 95.1%, with CR of 67.0%. Moreover, the ORR and CR rates were significantly worse in patients with elevated CRP (P= 0.007 and P= 0.049, respectively) and older age (P= 0.047 and P= 0.019, respectively).

The 5-year OS rate was 88.2%. In the univariate analysis, either elevated CRP, elevated LDH, PS ≥ 2, or histological grade 3a was significantly associated with poor OS (P= 0.002, P= 0.025, P= 0.004, and P= 0.011, respectively). In addition, high expression of Ki-67 with low expression of bcl-6 was associated with poor OS (P= 0.034), and high expression of Ki-67 tended to be associated with poor OS (P= 0.058). Both elevated CRP and histological grade 3a were still significantly associated with poor OS in the multivariate analysis (P= 0.026 and P= 0.013, respectively). The 5-year PFS was 54.0%. In the univariate analysis, elevated CRP and LDH were significantly associated with poor PFS (P= 0.001 and P= 0.022, respectively). Only elevated CRP was associated with poor PFS in the multivariate analysis (P= 0.012).

Among patients who were treated with the R-CHOP regime, the 5- year OS and PFS were 87.6% and 54.9%, respectively. In the univariate analysis, elevated CRP, elevated LDH, PS ≥ 2, histological grade 3a, and high expression of Ki-67 with low expression of bcl-6 were significantly associated with poor OS (P= 0.003, P= 0.028, P= 0.006, P= 0.016, and P= 0.046, respectively). Elevated CRP and histological grade 3a were significantly associated with poor OS in the multivariate analysis (P= 0.026 and P= 0.013, respectively). In the univariate analysis, elevated CRP and LDH were significantly associated with poor PFS (P < 0.001 and P= 0.009, respectively), and elevated CRP was associated with poor PFS in the multivariate analysis (P= 0.009). CRP was still significantly associated with poor OS and PFS.

Conclusions:

Our study found that elevated CRP levels before treatment were significantly associated with worse CR rates and poor OS and PFS in patients with FL treated with rituximab-containing regimens. Previous studies have reported that elevation of CRP levels is associated with poor OS or PFS in patients who were treated with rituximab combined with CHOP in DLBCL, but not FL. Our study indicates that serum CRP levels are important laboratory parameters for patients with FL who undergo rituximab treatment.