For years the standard treatment for patients with MCL has been polychemotherapy, usually based on adriamycin-containing regimens. CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) was the most popular regimen, with complete remission (CR) rates of 20–50% and a median overall survival (OS) of around 3 years. The intensive leukaemic regimen hyper-CVAD (a dose intense, hyperfractionated cyclophosphamide in a CHOP-like combination plus high-dose methotrexate and cytarabine) improved the results of CHOP in non-randomized studies. Fludarabine-containing regimens and other polychemotherapy combinations were also used with no substantial modifications on the outcome of the patients. More recently, the strategies for the management of MCL patients have changed due to the introduction of immunotherapy and new drugs that are more targeted to molecular mechanisms of the disease (Brody & Advani, 2006; Jares et al, 2007). The combination of chemotherapy regimens such as CHOP, hyperCVAD, or FCM (fludarabine, cyclophosphamide, mitoxantrone) with rituximab, a chimeric monoclonal anti-CD20 antibody with limited efficacy as a single agent, can produce impressive overall response rates of up to 80–95% and CR rates of up to 30–87% in previously untreated patients (Forstpointner et al, 2004; Lenz et al, 2005; Romaguera et al, 2005). Although the benefit in terms of OS seems more limited, a recent meta-analysis of randomized controlled trials supports the view that the combination of rituximab with chemotherapy might improve OS in MCL patients (Schulz et al, 2007). The immunotherapy with rituximab as maintenance therapy agent prolongs the response duration after combined rituximab-chemotherapy treatment (Forstpointner et al, 2006). When high-dose chemotherapy regimens or rituximab treatment are combined with autologous stem cell transplantation (autoSCT), preferentially in young patients, early in the course of the disease, and at first remission, high overall and complete response rates are reported, and a significant progression-free survival benefit compared with interferon maintenance have been reported in a randomized clinical trial (Gianni et al, 2003; Dreyling et al, 2005). However, relapse is the main concern, since there is not a plateau in the disease-free survival curves of these patients. Moreover, the impact on OS remains unclear, and longer patient follow-up is required in order to clarify the benefit of these therapeutic approaches. The use of high-dose therapy and allogenic stem cell transplantation (alloSCT), that would have much higher eradicative capacity, is unsuitable for most MCL patients due to the need of good patient performance and the high treatment related mortality. To overcome this high toxicity, nonmyeloablative alloSCT regimens have been developed and could represent an option in patients with relapse mantle-cell lymphoma (Khouri et al, 2003). Recent reports in refractory/relapsed MCL patients showed high responses rates, with progression-free survival of 30–60%, OS 45–65% and related mortality below 30% (Maris et al, 2004; Corradini et al, 2007).
Nonetheless, despite the high rate of response achieved by these multimodal approaches, the majority of patients relapse, meaning that MCL patients are not cured by conventional therapy strategies. The need of novel therapeutic approaches and the increasing understanding of the MCL cell biology have led to the development of new therapeutic agents with antitumour activity that target crucial biological pathways, including cell cycle inhibitors (Flavopiridol, R-roscovitine, UCN-01 and styril sulfones), proteosome inhibitors (Bortezomib), mTOR inhibitors (Sirolimus, Temsirolimus, Everolimus) and histone deacetylase inhibitors (SAHA) among others. These new therapeutic approaches are being investigated in preclinical and preliminary clinical trials with promising results in patients previously treated with aggressive regimens (Kouroukis et al, 2003; Goy et al, 2005; O’connor et al, 2005). The combination of these new strategies with other therapeutic agents, including standard chemotherapy drugs (Haritunians et al, 2007; Weigert et al, 2007), and the correct stratification of the patients according to the specific biological risk of each case may change the management and outcome of MCL patients.