Translational evaluation of innovative therapeutic strategies and molecular prognostic factors.

Mantle cell lymphoma (MCL) is a distinct, clinically very aggressive subentity of malignant lymphoma with a median survival of 3 years. However, a small subset of patients represents long-term survivors. So far, the discriminative power of different prognostic parameters has been limited and did not allow the reliable identification of the individual patient's risk profile. Thus, a better understanding of the underlying molecular mechanisms is eagerly warranted. In the last few years, European-wide MCL networks of clinicians (Clinical MCL Intergroup Working Party), pathologists (European MCL Pathology Panel) and basic researchers (European MCL Research Network) have been established to investigate the clinical as well as molecular aspects of malignant transformation and progression in MCL. Especially, strict diagnostic histomorphological criteria have been defined; in a prospective randomized study, an intensive consolidation with high dose radiochemotherapy and subsequent autologous stem cell transplantation resulted in superior progression-free and overall survival rates; and most interestingly, proliferation indices have been identified as the most important prognostic factors in MCL superior to clinical parameters (IPI). Based on these extensive prerequisites and the recent development of innovative molecular techniques (matrix CGH, RNA array chips, RQ-PCR, proteomics), we propose a global approach to investigate innovative treatment options of MCL and evaluate new predictive (pharmacogenomics, minimal residual disease) and prognostic molecular markers (genomic alterations, RNA/proteome profiles) in such controlled studies. This translational approach of the European MCL Network will not only lead to more individualized therapeutic strategies based on a molecular risk profile but will also finally elucidate the way to future molecular targeted treatment options in a subtype of malignant lymphoma with an otherwise dismal clinical outcome.