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