Response Continues for at Least 8 Months with Ibritumomab Tiuxetan

ROCHESTER, Minnesota—More than half of follicular non-Hodgkin’s lymphoma (NHL) patients who progress after rituximab (Rituxan) treatment respond to the experimental drug ibritumomab tiuxetan (Zevalin), according to a multicenter clinical trial. Although most of the study’s 54 patients had only partial remissions after treatment with ibritumomab tiuxetan, their response continued for at least 8 months. In some cases, remissions have lasted up to 2 years.

Ibritumomab tiuxetan is the monoclonal antibody rituximab used in conjunction with the radioactive isotope yttrium 90. Although the FDA approved rituximab, trials on ibritumomab tiuxetan for submission to the FDA are ongoing.

"The study helps show that using Zevalin—adding a radioactive particle to the monoclonal antibody rituximab—does improve response rate," said lead investigator Thomas E. Witzig, MD, hematologist and internist at the Mayo Clinic in Rochester, Minnesota.

Although 59% of follicular NHL patients had confirmed complete or partial remissions according to a Lymphoma Expert Confirmation of Response (LEXCOR) panel, objective response rates using the International NHL Response Criteria were as high as 74%, Dr. Witzig reported.

Studies of rituximab alone show that the response rate in relapsed low- grade NHL patients is 50%. A 1999 study of ibritumomab tiuxetan produced response rates of 82% among NHL patients. "These studies raised the question of whether or not the radiolabeled conjugate yttrium 90 could be increasing efficacy when added to the monoclonal antibody rituximab," Dr. Witzig said.

Response and Duration

The current trial compared response rates and duration of response on ibritumomab tiuxetan vs rituximab and prior chemotherapy treatments. Patients in the study were a median of 54 years old and 32% had bone marrow involvement. Seventy-four percent of patients had significant bulky disease and half were classified as having intermediate- to high-risk disease. Patients must have had no response to prior rituximab treatment, or a partial or complete response that lasted less than 6 months.

The duration of response on ibritumomab tiuxetan was at least 7.7 months, though the median had not yet been reached by the end of the trial. Those who progressed after ibritumomab tiuxetan treatment did so after a median of more than 9 months.

The investigators also asked another important question. How did patients who had responded to rituximab for a short time do after ibritumomab tiuxetan treatment? Study data showed that 31% of patients had a short partial or complete remission after rituximab treatment. Among responders to rituximab, 76% had partial or complete remissions on ibritumomab tiuxetan. Not surprisingly, those who did not respond to rituximab had a response rate to ibritumomab tiuxetan of just 51%.

Those who had remissions on rituximab also had 8+ months duration of response to ibritumomab tiuxetan, though the median had not been reached by the end of the trial. These same patients, however, had a median response rate of just 4 months on rituximab.

Excellent Tolerability

Ibritumomab tiuxetan also measured up to the patients’ previous chemotherapy treatment in this study.

Patients had been heavily pretreated with a median of four prior regimens. Sixty-six percent had responded to their last chemotherapy treatment, compared to the 59% remission rate with ibritumomab tiuxetan, a difference that was not statistically significant, Dr. Witzig said. "We know now that Zevalin was just as good as these patients’ last chemotherapy sessions," he added.

Patients who were responders to chemotherapy were also more successful on ibritumomab tiuxetan. Those who had remissions with chemotherapy had a 65% response rate on ibritumomab tiuxetan and those who were resistant to chemotherapy had a 47% ibritumomab tiuxetan response rate.

Of those who responded to chemotherapy, the duration of response was 5 months, while this same group of patients had a response rate of 6 months on ibritumomab tiuxetan.

Most of the side effects of the Zevalin treatment were hematologic, transient, and reversible, Dr. Witzig said. There was no liver, lung, or kidney toxicity, and only 7% of patients required hospitalization for infection. One patient developed human antibodies to the murine antibody (HAMA).

Hemoglobin and platelet counts of patients reached a nadir at 7 to 8 weeks and took 1 to 2 weeks longer to recover. "We can conclude from this data that Zevalin is safe and effective in patients who fail rituximab," Dr. Witzig said.