BETHESDA, MdIt is widely assumed that monoclonal antibodies will not work in bulky non-Hodgkins lymphoma (NHL) because such agents require direct contact with target antigens expressed on tumor cell surfaces and cannot reach antigens inside tumor masses. Phase II data reported at ASH indicate this may not be true for rituximab(Drug information on rituximab) (Rituxan).
Thomas Da-vis, MD, of the NCI, cited an overall response rate of 43% in 28 patients with bulky progressive low-grade or follicular NHL treated with rituximab. The trial included 31 patients with at least one lesion of 10 cm or greater and a median of three prior therapies; 68% of patients had stage III/IV disease. Rituximab was given at 375 mg/m²/wk for 4 weeks.
Twelve of 28 evaluable patients responded (43%), including one CR. Median response duration was 5.9 months, with four responses ongoing at 11+ to 12.1+ months. B symptoms resolved in 8 of 10 patients. Some patients had lots of disease, which just disappeared. I expected to see some partial remissions, but the CR was a surprise, he said. The overall response rate in patients with IWF B, C, or D disease was 55% (12 of 22). There was no correlation between response and number of relapses, number of prior chemotherapies, or chemoresistance.
Most treatment-related adverse events were mild to moderate, usually at the first infusion. Four patients had grade 3-4 nonhematologic toxicity. One died with bronchiolitis obliterans 10 months post-treatment, but the relationship to rituximab is unclear. Seven patients had transient grade 3-4 hematologic toxicity, but there were no grade 3-4 infections. No patients developed HACA.
How Does It Work?
How does the antibody work in bulky NHL? This is a chimeric antibody that stays in the system for months, Dr. Davis said. Even though it may not be able to penetrate bulky tumors at first, as the tumor shrinks, the antibody may attack its next layer.
Antonio Grillo-López, MD, of IDEC Pharmaceuticals, which makes rituximab, suggested that in addition to apoptosis, antibody-dependent cellular cytotoxicity (ADCC) may be an important mechanism. The part of the tumor shrinkage due to ADCC is dependent on the number of effector cells present and on how capable they are. If you give the antibody and have massive depletion, you are probably going to exhaust those effector mechanisms. As they start to recover, there may be more shrinkage.
In some patients, shrinkage continues for up to 19 months, slowly and gradually. That is very different from the response curve with chemotherapy, he said.
Based on these data, Dr. Davis said, I would not hesitate to use rituximab in bulky disease. Future trials will not automatically exclude bulky disease.