Adding Radioactivity to an Anti-CD20 Antibody Increases the Response Rate Compared to CD20 Alone

ROCHESTER, Minnesota—Adding a radioactive antibody aimed at the CD20 antigen to rituximab (Rituxan), a chimeric anti-CD-20 antibody, raised overall response rates to 80% and complete response rates to 21% in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). Preliminary data from this multicenter trial was reported at the ASH meeting by Thomas E. Witzig, MD, of the Mayo Clinic.

The prospective, randomized, controlled trial compared the effects of a standard course of rituximab to rituximab plus ibritumomab tiuxetan (Zevalin, IDEC-Y2B8). This is an anti-CD20 murine immunoglobulin-G (IgG) monoclonal antibody conjugated to tiuxetan, which can securely chelate either indium 111 for imaging or dosimetry, or yttrium 90 for radioimmunotherapy. Rituximab, which is derived from ibritumomab, binds complement and induces both complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Both antibodies can induce apoptosis.

First 90 Patients

All 143 patients enrolled in the trial had relapsed or refractory low-grade, follicular, or transformed CD20+ B-cell NHL. Patients were randomized either to standard rituximab or to rituximab plus Y2B8 (see Table 1). There were no significant differences in the randomized groups at baseline with regard to median age, bone-marrow involvement, splenomegaly, bulky disease, prior therapy, chemotherapy resistance, or International Prognostic Index.

“Patients were randomized to receive either rituximab weekly for 4 weeks or rituximab on days 0, 7 and IDEC-Y2B8 on day 7,” Dr. Witzig said in an interview. “The Y2B8 treatment as tested in our phase I/II trial consists of the two doses of rituximab

and the one dose of Y2B8. The rationale for giving the rituximab is to bind nonspecific CD20 sites so that the Y2B8 goes primarily to the tumor.”

Dr. Witzig reported that data on the first 90 patients randomized and treated showed an overall response rate (ORR) of 80% for the combination arm, with a complete response (CR) rate of 21% and a partial response (PR) rate of 59%. For the rituximab only arm, ORR was 44% (7% CR, 37% PR, P <.001). In addition to the Mayo Clinic, patients were recruited by investigators at Northwestern University in Chicago, the University of Texas M. D. Anderson Cancer Center in Houston, Roswell Park Cancer Center in Buffalo, N.Y., the Cleveland Clinic and other sites.

Results as Predicted

“The results came out as predicted by the respective single-agent phase II trial of each compound,” Dr. Witzig said. Analysis of response durability is not yet possible.

“We believe that the difference [in efficacy] is due to the radioactivity delivered by the yttrium 90 that is attached to the anti-CD20 antibody,” Dr. Witzig explained. “Yttrium has a path length of about 5 mm. Therefore, when the antibody binds to the CD20+ B-cells, it radiates not only to those cells but the cells in the immediate area (Figure 1).”

Final data from this study are expected in mid-2000. Wider clinical use of this regimen will, however, require some special skills. “The hematologist/oncologist will need to work with physicians in either nuclear medicine or radiation therapy who have expertise in handling the radioactive antibody,” Dr. Witzig said.

The investigators were pleased with the higher response rate produced by the rituximab/Y2B8 combination. “However, we would like to see an even higher complete remission rate than the 21% rate seen in this study,” Dr. Witzig said. “New trials in the next year will be delivering a second dose of Y2B8 after the blood counts have stabilized to see if we can further improve on the CR and the duration of response.”