Radioimmunotherapy of Relapsed Non-Hodgkin's Lymphoma with Zevalin, a 9~ Anti-CD20 Monoclonal Antibody

Approximately 55,400 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year, with the overall prevalence of the disease now estimated to be 243,000. Until recently, treatment alternatives for advanced disease included chemotherapy with or without external beam radiation. Based on the results of several clinical trials, the chimeric monoclonal antibody Rituximab has now been approved by the United States Food and Drug Administration as a treatment for patients with relapsed or refractory, low-grade or follicular, B-cell NHL. Several other monoclonal antibodies in conjugated and unconjugated forms have been evaluated in the treatment of NHL. Ibritumomab, the murine counterpart to Rituximab, radiolabeled with 9Oy (Zevalin), is presently being evaluated in clinical trials. The success of radioimmunotherapy is dependent upon the appropriate choice of antibody, isotope, and chelator-linker. The Ibritumomab antibody targets the CD20 antigen. The antibody is covalently bound to the chelator-linker tiuxetan (MX-DTPA), which tightly chelates the isotope 9Oy. To date, two Phase I/II Zevalin clinical trials have been completed in patients with low-grade, intermediate-grade, and mantle cell NHL. The overall response rate was 64% in the first trial and 67% in the later trial. Phase II and III trials are ongoing. Introduction Approximately 55,400 new cases of NHL 3 are diagnosed each year, with the overall prevalence of the disease now estimated to be 243,000. Until recently, treatment alternatives for patients with advanced-stage NHL included only chemotherapy with or without external beam radiation. Unfortunately, relapsed NHL is rarely, if ever, curable, and remissions are less likely and shorter with each subsequent course of therapy. High-dose therapy has been developed, in part, to overcome tumor cell resistance, but it is accompanied by heightened toxicity for the patient. Antibody therapy with or without conjugated radionuclides offers an alternative to traditional treatment, with the possibility of decreased toxicity (1). Monoctonal antibodies have evolved considerably since the years following K6hler and Milstein's development of hybridomas. Whereas some responses were observed in early clinical studies with murine antibodies, therapy was often limited by the development of HAMA, the relative inability of mouse antibodies to recruit human immune effector mechanisms for tumor killing, and down-regulation of target antigens