Randomized Clinical Trial to Evaluate Maintenance Therapy in Diffuse Large Cell Lymphoma Treated with Intensive Chemotherapy

Although complete response (CR) rate has been increased with the use of more intensive and in some cases myeloblative chemotherapy, long term follow-up has shown that relapse continues to be a major problem in patients with diffuse large cell lymphoma. Maintenance therapy is not considered as standard therapy in this group of patients. In our experience, the use of maintenance therapy either with low-doses of cyclophosphamide and prednisone (C/P) or interferon-α2b (IFN) improves the duration of event free survival (EFS) and overall survival (OS) in patients treated with conventional chemotherapy. The use of more intensive chemotherapy increases the CR rate, but does not effect EFS and OS. We therefore started a controlled clinical trial to assess the efficacy and toxicity of maintenance therapy with C/P or IFN in patients on CR after intensive, non myeloablative, chemotherapy. From January 1994 to December 1996; 269 patients with diffuse large cell lymphoma (defined as patients with high- or high-intermediate clinical risk) were allocated to receive C/P (200mg/m 2 , po, daily, by 5 days and 50 mg/m 2 , po, daily, by 5 days, respectively, every 6 weeks by 2 years) or IFN: 5 MU three times at week by 1 year compared to a control group. In an intent to treat analysis, 269 patients were eligible for study. All were evaluated for EFS and OS. The median follow-up is 49.6 months. A comparison of the three groups revealed no significant differences on EFS: 72% (95% CI: 60% to 77%) for IFN arm; 71% (95% CI: 62% to 82%) for C/P group and 74% (95% CI: 68% to 85%) in the control group (p =.8). Also OS was not different: 70% (95% CI: 59% to 79%); 68% (95% CI: 60% to 78%) and 72% (95% CI: 63% to 78%) respectively (p =.750). All patients completed the programmed schedule. Toxicity was mild. Previously we demonstrated that maintenance therapy is useful in patients with aggressive malignant lymphoma when they were treated with conventional chemotherapy. However, when more intensive chemotherapy was used to achieve CR, maintenance therapy was not useful. We do not have a convincing explanation. We believe that intensive chemotherapy may eradicate all sensitive cells to drugs, such as IFN or C/P, and for this reason improve survival was not observed. On the other hand, in patients treated with conventional chemotherapy, some residual and sensitive tumor cells must remain and maintenance therapy may eliminate this cells, with improvement in EFS and OS. Long term follow-up is