HAMA Response in Iodine I 131 Tositumomab Patients Does Not Preclude Use of Rituximab

SOUTH SAN FRANCISCO—A new study reveals that patients who develop HAMA (human antibodies to the murine antibody) after treatment with iodine I 131 tositumomab (Bexxar) do not develop cross-reactive antibodies or immune reactions that would interfere with later treatment with rituximab (Rituxan).

Iodine I 131 tositumomab radioimmunotherapy consists of an anti-CD20 murine monoclonal IgG2a antibody and its radiolabeled conjugate iodine I 131. Iodine I 131 tositumomab has been shown to be effective in patients with both relapsed/refractory and previously untreated non-Hodgkin’s lymphoma. It is among previously untreated patients that HAMA frequently develops and can cause allergic or flu-like symptoms. It could also potentially decrease efficacy of antibody treatments, such as rituximab, a chimeric antibody containing murine Ig sequences.

"We wanted to know if HAMA developed after Bexxar therapy would cross-react to rituximab, affecting the patients’ safety and future efficacy of treatment," explained Matthew Nieder, PhD, senior scientist at Corixa Corporation (formerly Coulter Pharmaceuticals) in South San Francisco, California. "We found that the patients we treated who subsequently developed HAMA positivity experienced no cross-reactivity to rituximab. These patients experienced the infusion reactions commonly associated with rituximab, with no increase in severity." Corixa Corporation is developing Bexxar.

Cross-reactivity Tested

The study was conducted with patients at the University of Michigan, with Mark Kaminski, MD, serving as the lead researcher. Serum samples of 22 patients who had developed HAMA greater than 500 ng/mL after treatment with iodine I 131 tositumomab were tested for cross-reactivity with rituximab and for the presence of anti-chimeric antibodies (HACA). Six of these patients were later treated with rituximab—two without intervening chemotherapy. There was no evidence of increased severity or frequency of infusion-related events symptomatic of an immune reaction.

This study follows a previous report of six patients who had become HAMA positive after iodine I 131 tositumomab therapy and were later treated with rituximab. These six showed no unexpected flu-like symptoms. That study appeared in the Annals of Oncology 10:(suppl 3):33, 1999.

In the most recent study, the patients’ serum samples were obtained from the time of peak HAMA positivity (13-482 days following therapy). The assays used to assess HACA measure binding to rituximab by using goat antimouse IgG (ab')₂ as a standard. The test was sensitive enough to detect 250 ng/mL HACA in human serum.

Patients received a therapeutic dose of 450 mg tositumomab and a patient-specific mCi amount of iodine I 131 tositumomab, delivering a 75 cGy total body dose. Forty-nine of a group of 76 patients (64%) who received iodine I 131 tositumomab as a frontline therapy developed a HAMA response. But only 7% of previously treated patients with relapsed/refractory low-grade or transformed low-grade NHL developed HAMA after treatment with iodine I 131 tositumomab. Patients who have had chemotherapy previous to receiving tositumomab generally lose the ability to generate HAMA antibodies, Dr. Nieder explained.

100% Nonbinding Antibodies

"There have been concerns about using a murine-containing antibody such as rituximab in patients who have developed HAMA," Dr. Neider said. This study showed that the HAMA did not bind to rituximab, thus preserving a treatment option for HAMA positive patients.

"The big issue for us was whether or not these antibodies were binding to rituximab. And the results showed that the antibodies were 100% nonbinding," Dr. Nieder said.

"Our study indicates that receiving rituximab after Bexxar is safe."

A separate study conclusively showed that iodine I 131 tositumomab can be safely and effectively administered to NHL patients following rituximab.