Abstract

Background: Mantle cell lymphoma (MCL) shows a particularly bad prognosis with a median survival of less than 5 years. There is no generally established prognostic classification system for patients with MCL as the International Prognostic Index (IPI) and the Follicular Lymphoma International Prognostic Index (FLIPI) have been developed based on data of patients with diffuse large B-cell and follicular lymphoma, respectively. The data of 455 patients with advanced stage MCL treated within three randomized trials of German Low-Grade Lymphoma Study Group (GLSG) and European MCL Network were used to clarify the prognostic relevance of IPI, FLIPI and potential prognostic factors and, if needed, to develop a new prognostic index. Methods: The outcome parameter was overall survival, the time from trial registration to death from any cause. Potential prognostic factors were the clinical parameters documented after primary diagnosis before start of treatment. The prognostic relevance of IPI and FLIPI was evaluated with Kaplan-Meier estimates and the log rank test. Candidate prognostic factors were analyzed using univariate Cox regression. In multiple Cox regression, independent prognostic factors were identified with backward elimination and the prognostic score was determined. Prognostic groups were defined with optimal cutpoints for the prognostic score maximizing the log rank statistic. Internal validation was performed using the bootstrap method. Results: According to the IPI more than two thirds of patients were classified into the low intermediate or high intermediate risk groups whose survival curves were not clearly separated. According to the FLIPI, 6% of patients were classified into the low risk group, survival curves of low risk and intermediate risk patients were not separated, and the high risk group of almost two thirds of patients showed a relatively good survival. Of the candidate prognostic factors, age, ECOG performance status, B-symptoms, spleen involvement, tumor size, serum LDH activity, leukocyte, lymphocyte, granulocyte and monocyte count, hemoglobin, and beta2-microglobulin showed univariate prognostic relevance. In contrast, sex, Ann Arbor stage III vs. IV, bone marrow involvement, number of extranodal sites, number of involved nodal areas, platelet count, and albumin showed no prognostic relevance. Multiple Cox regression identified age, performance status, LDH and leukocyte count as independent prognostic factors. Using these four parameters, a new prognostic index, the mantle cell lymphoma international prognostic index (MIPI) defined three prognostic groups with significantly different overall survival. Bootstrap validation confirmed the separation of the prognostic groups and indicated superiority over IPI and FLIPI. Conclusions: In this work a new prognostic index for patients with advanced stage MCL was defined based on four easily available clinical prognostic factors. The modest prognostic relevance of IPI and FLIPI underlines the inappropriateness of transferring results from one lymphoma entity to another. The results of this work may be applied in clinical research for stratified randomization, risk-adjusted analyses, and as a reference to establish new biologic or molecular prognostic factors. Furthermore, the new prognostic index may facilitate risk-adapted treatment strategies to improve the prognosis of this severe disease.