This project is based on the hypothesis that treatment of mantle cell lymphoma may be improved by targeting both the lymphoma cells and the microenvironment, i. e. the presumably normal stromal cells of the lymph node and the bone marrow surrounding the malignant cells.
The first evidence for efficacy of such a treatment strategy came from our observations with thalidomide plus rituximab. We have updated our results with thalidomide plus rituximab in patients with relapsed mantle cell lymphoma (MCL) (patients had previously undergone treatment with standard CHOP or a CHOP-like regimen, three had received high-dose therapy). Of the 18 patients, 15 responded, and 5 of those responses were complete, with some lasting up to 30 months. The median time to disease progression among the study patients was 20 months. Most notably, time to progression in the study was longer compared to that after the preceding chemotherapy, an observation rarely encountered in oncology. Two patients are in ongoing complete remission (54 and 48 months, respectively, after study entry).
Based upon these encouraging results, we have started our new trial, which evaluates the efficacy of rituximab plus CHOP plus thalidomide in patients with newly diagnosed MCL (18 patients enrolled to date). A planned safety analysis after the first 10 patients did not reveal an unexpected rate of severe adverse events (in particular with respect to polyneuropathy and venous thromboembolism). Among these patients, we have observed 8 complete and 2 partial remissions. Recruitment is ongoing, with time to disease progression as primary study endpoint.
Laboratory studies are underway to further study the mechanisms responsible for the augmented antitumor activity observed in MCL patients treated with thalidomide.
Despite the efficacy observed in our study, MCL remains a difficult-to-treat entity, and novel therapeutic strategies need to be evaluated. We have therefore expanded our concept of targeting both tumor cells and microenvironment by including the novel proteasome inhibitor bortezomib. A treatment program combining bortezomib, rituximab, and dexamethasone (BORID) has been initiated for patients with relapsed and chemotherapy refractory MCL (recruitment of 7 patients to date).
