Early Consolidation with Myeloablative Radiochemotherapy Followed by Autologous Stem Cell Transplantation in First Remission in Mantle Cell Lymphoma: Long Term Follow up of a Randomized Trial of the

Abstract

Background: Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma with an especially poor prognosis and a median survival of only 3–4 years.Methods: In 1996, the European MCL Network initiated a randomized trial to improve the dismal outcome of MCL, comparing early consolidation with myeloablative radiochemotherapy (TBI 12 gray, cyclophosphamide 120 mg/kg bw) followed by autologous stem cell transplantation (ASCT) to a conventional α-interferon maintenance (6×106 IE IFN- α3x weekly) in first remission after a CHOP-like induction regimen (Dreyling et al, Blood 2005). Here we report the long term results of this prospective trial.Results: Until March 2004, a total of 232 previously untreated patients up to 65 years with advanced stage MCL were randomized upfront. 173 (76%) of 228 patients evaluable according to the intention to treat (ITT) responded to initial induction chemotherapy and 151 of these (87%) proceeded to the assigned consolidation therapy. 144 patients were evaluable per protocol, 75 pts in the ASCT arm and 69 patients in the IFN maintenance arm. Baseline characteristics were comparable in the per protocol as well as in the ITT cohorts. Patients in the ASCT study arm experienced a significantly longer response duration (RD, median 3.7 years) as compared to patients in the IFNa arm (median 1.6 years, p = 0.0004). These differences were even more pronounced in the CR patients (median response duration 4.5 years vs. 1.6 years) and the intent to treat analysis (median time to treatment failure 2.6 vs. 1.4 years, p = 0.0001). Most importantly, this advantage resulted in a pronounced trend towards an improved overall survival (OS) in the ASCT arm. After a prolonged follow-up of up to 10 years (median 6.1 years), median survival after ASCT was 7.5 years in comparison to 5.4 years under IFN-α maintenance (p = 0.075). In the intent to treat analysis median OS was 7.5 vs. 5.3 years (p = 0.031). As expected, acute toxicity was higher in the ASCT group, whereas long-term effects were more frequently encountered under IFN-α maintenance.Conclusion: In first line treatment of advanced stage MCL, dose-intensified consolidation with myeloablative radiochemotherapy followed by ASCT after CHOP-like induction results in a significantly prolonged response duration and may also result in an improved overall survival. Accordingly, dose-intensified regimens represent the current therapeutic standard in younger MCL patients. Future study concepts will evaluate the addition of molecular targeted approaches to further improve long term outcome.