ANN ARBOR, MichiganA radiolabeled monoclonal antibody was more effective than previous chemotherapy had been in more than half of patients with indolent lymphomas, in a study reported at the American Society of Hematology meeting.
Mark S. Kaminski, MD, and his colleagues at the University of Michigan Cancer Center, Ann Arbor, and other major centers conducted a phase III study of Coulter Pharmaceuticals investigational agent, Bexxar (iodine-131 tositumomab) for chemotherapy-refractory low-grade or transformed low-grade non-Hodgkins lymphoma (NHL).
Inexorable Relapse Rate
Dr. Kaminski said that work with the antibody was undertaken in an attempt to overcome the inexorable relapse rate following chemotherapy in this type of cancer, in which the duration of response becomes shorter and shorter with each succeeding round of chemotherapy (see Figure 1).
The new agent is a radiolabeled murine IgG2a monoclonal antibody directed against the CD20 antigen on B cells. CD20 is thought to be a good target because it is membrane-bound, is not shed, and is present in 95% of B-cell NHL. CD19 and CD22 are also potential targets for this type of therapy (Figure 2).
Dr. Kaminski said that tositumomab is a promising antibody because it triggers apoptosis, recruits the immune system response, inhibits B-cell proliferation, and induces antibody-dependent cellular cytotoxicity.
Radioconjugated antibodies have attracted attention because they may have a crossfire effect and thus may be able to kill nearby antigen-negative tumor cells as well as those expressing the target antigen.
Potential disadvantages of a radiolabeled monoclonal antibody include the possible need for patient isolation; potentially dose-limiting toxicity (myelosuppression); and toxicity or development of a HAMA (human antimouse antibody) response that may limit re-treatment with the antibody or future treatment with other therapies.
Eligible patients had low-grade or transformed lymphoma, had received two or more prior chemotherapy regimens, and had failed to respond or had responses lasting less than 6 months on the last therapy.
Sixty patients were enrolled in the study, 36 (58%) with low-grade NHL; 23 (40%) with transformed low-grade NHL; and one (2%) with mantle cell lymphoma. On their last previous regimen, only 3% of patients had a complete response, and 25% had a partial response. The median number of prior regimens was four.
The primary study endpoint was the difference in efficacy between 131I-tositumomab and the last qualifying chemotherapy using patients as their own controls, Dr. Kaminski said.
A single dosimetric dose (450 mg of unlabeled antibody) was given IV, followed by 35 mg of antibody radiolabeled with 5 mCi of iodine-131. Gamma camera counts were used to calculate the required activity (mCi) to deliver the desired therapeutic dose (65 cGy to the whole body for patients with platelet counts between 100,001/mm³ and 149,999/mm³, and 75 cGy for patients with platelets of 150,000/mm³ or more).
The single therapeutic dose (450 mg of unlabeled antibody IV over 1 hour followed by 35 mg of radiolabeled antibody over a half hour) was given 7 to 14 days after the dosimetric dose.
Dr. Kaminski reported responses in 39 of 60 patients (65%) after 131I-tositumomab, compared with 17 of 60 (28%) after the last previous chemotherapy regimen (P < .0001). Complete responses were seen in 17% of patients after antibody therapy vs 3% for the last previous therapy (P = .01). Responses were assessed by a masked randomized review of efficacy data by an independent panel of radiologists and clinicians.
Median duration of response was 6.5 months after 131I-tositumomab vs 3.5 months after the previous chemotherapies, perhaps indicating a reversal of the natural history of the disease with this therapy, Dr. Kaminski said.
Responses vs Previous Chemo
Thirty-two patients had a better response to 131I-tositumomab than to previous chemotherapy; 19 had an equivalent response; and 9 had an inferior response.
Myelosuppression was the main toxicity, but nadir neutrophil counts less than 100/mm³ and platelet counts less than 10,000/mm³ occurred in only 2% of patients, Dr. Kaminski said. The nadirs typically occurred at week 5 or 6 with recovery by week 8 or 9. The main nonhematologic toxicities were fatigue, fever, and nausea. There was one treatment-related infection but no deaths. Four patients (7%) developed HAMA.