A Novel Hierarchical Prognostic Model Based on Clinical Feature and Cytogenetics for Splenic Marginal Zone Lymphoma

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell neoplasm, which often involved with spleen, bone marrow (BM), and sometimes involved with the peripheral blood. However, the clinical characteristics of Chinese SMZL patients remain elusive.. This present study is undertaken to systematically analyze the clinical and biological characteristics of SMZL in Chinese patients, and draw out an appropriate hierarchical prognostic model of SMZL in the rituximab era.

Method: A total of 172 patients with newly diagnosed SMZL in Institute of hematology and blood disease hospital were retrospectively analyzed. Clinical characteristics, including flow cytometry analysis of tumor cells, immunohistochemistry, cytogenetics and molecular detection data were collected and IgHV mutation status, fluorescence in situ hybridization (FISH) data were carried out on patients with available samples.

Result: The median age at diagnosis of 172 patients with SMZL was 57 years (range 25-81) and male having little prominence (52.3%). Using a homology cut-off value of 98% to the nearest germline gene, we observed mutated IGHV in 29 (74.4%) and unmutated IGHV in 10 (25.6%) of the 39 SMZL patients. The most frequently used fragments of IGHV gene were IGHV1-2 (25.6%), IGHV4-34 (15.4%), IGHV2-27 and IGHV3-30 (10.3% and 7.8% respectively). The 49.0% patients had HBV infection currently or before SMZL diagnosis, and 14.6% with active HBV infection. Chromosomal aberration was noted in 21.2% patients and 14.4% patients have complex karyotype (more than three aberrations). The FISH detection indicated that the cytogenetic aberrant of 13q- (Rb1/ D13S25), trisomy 12, 17p-(TP53) and t(14q32) was 9.8% (8/82), 9.6% (8/83), 4.7% (6/126) and 20.4% (19/93), respectively. Among those patients, 64 patients (41.6%) received rituximab-based immunochemotherapy as the first line treatment and other 37 patients (24.0%) with conventional chemotherapy treatment alone.

With a median follow-up of 50.5 months (range, 6-214 months), the estimated 5-year failure-free survival (FFS) and overall survival (OS) rates were 74.6% and 80.8%, respectively. The 5-year FFS for patients with rituximab-based treatment was significantly prolonged than those rituximab-free treatment patients (89.9% vs 60.9%, P = 0.005). Based on the univariate analysis, the significant predictive parameters for shorter OS included hemoglobin level <11 g/dl (p=0.000), HBVs-Ag positivity (p=0.001), FLIPI 4-5 (p=0.000), trisomy 12 (p=0.004), chromosomal aberration (p=0.007), complex karyotype (p=0.001) and ECOG 2-4 (p=0.005). A Cox regression model of OS revealed that hemoglobin level <11 g/dl, HBV-Ag positivity, complex karyotype were the independent prognostic factors (p=0.045, 0.044 and 0.002, respectively). Of note, only HBVs-Ag positivity and complex karyotype aberrant had a negative influence on OS even after adjusted by rituximab treatment.

Using above 3 independent variables, we identified a novel hierarchical prognostic model with three risk groups: low-risk group (39.2%) with no adverse factors, intermediate-risk group (38.6%) with one factor and high-risk group (22.1%) with 2 or 3 factors. The 5-year OS was 96.7%, 78% and 53.3%, respectively (p=0.000). The 5-year FFS was 95%, 67.5% and 39.4%, respectively (p=0.000). The novel hierarchical prognostic model showed an advanced c-index than the other risk models, including IPI, FLIPI and the tradition SMZL score significantly.

Conclusion: Chinese patients with SMZL have distinct clinical characteristics. The novel prognostic index system composed of hemoglobin, HBVs-Ag and complex karyotype aberrant could effectively stratify the outcomes of patients with SMZL and appears to be a promising risk model for Chinese SMZL patients in the rituximab era.