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 (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.