Abstract

Clinical trials of an yttrium-90 (90Y)-conjugated monoclonal antibody to CD20 in patients with relapsed B cell non-Hodgkin lymphoma (NHL) are reviewed. Ibritumomab is the murine parent anti-CD20 antibody engineered to make the human chimeric antibody rituximab. Tiuxetan is an MX-DTPA linker chelator attached to ibritumomab to form ibritumomab tiuxetan (Zevalin). Ibritumomab tiuxetan can react with indium-111 (111In) or 90Y to form 111In-ibritumomab tiuxetan, which is used for dosimetry, or 90Y-ibritumomab tiuxetan, which is used for therapy of B cell NHL. In this report, the results of five separate clinical trials of ibritumomab tiuxetan are reviewed. Two phase I trials of 90Y-ibritumomab tiuxetan were performed, one using cold ibritumomab prior to 90Y-ibritumomab tiuxetan, and one using rituximab prior to 90Y-ibritumomab tiuxetan. The optimal schedule was found to be rituximab on days I and 8, and 90Y-ibritumomab tiuxetan 0.4 mCi/kg i.v. on day 8; no stem cells or prophylactic growth factors were used. A dose of 0.3 mCi/kg was recommended for patients with a baseline platelet count of 100,000-149,000x10(6)/l. The only significant toxicity was reversible myelosuppression. With this schedule, the overall response rate (ORR) was 67% of all patients and 82% of those with low-grade NHL. The phase I/II trials were followed by a phase III trial that randomized 143 eligible patients to either rituximab or 90Y-ibritumomab tiuxetan radioimmunoconjugate to demonstrate that the combination of the 90Y radioisotope to the murine anti-CD20 antibody provided additional efficacy over the unconjugated ("cold") rituximab alone. A planned interim analysis of the first 90 patients demonstrated an ORR of 80% with 90Y-ibritumomab tiuxetan vs 44% for rituximab (P < 0.05). To provide additional evidence of the benefit of 90Y radioimmunotherapy over rituximab immunotherapy, patients who were nonresponsive or refractory to rituximab were enrolled in an additional trial and treated with 90Y-ibritumomab tiuxetan 0.4 mCi/kg. An ORR of 46% was achieved in these rituximab-refractory patients. These results provide further evidence of the added value of 90Y. Therefore 90Y-ibritumomab tiuxetan radioimmunotherapy is a useful new treatment modality for patients with B cell NHL. Future trials are needed to define the optimal time in the disease course when this modality should be used.