Iodine-131 tositumomab (Bexxar), a radiolabeled immunoglobulin G2a (IgG2a) monoclonal antibody directed against the CD20 antigen, is effective in the treatment of previously untreated, as well as relapsed and refractory, low-grade and transformed, low-grade non-Hodgkins lymphoma (NHL). Fludarabine (Fludara) is also active as a single agent or in combination in NHL. In vitro data have shown that iodine-131 tositumomab and fludarabine have a markedly supraadditive effect on tumor cell killing.
We are evaluating the safety and efficacy of a sequential regimen of three cycles of fludarabine (25 mg/m² × 5 d q5wk) followed, 6 to 8 weeks later, by tositumomab and iodine-131 tositumomab for patients with previously untreated, low-grade, transformed, low-grade or follicular NHL. A total of 38 patients were enrolled, 14 of whom are evaluable for response at least 3 months post-treatment with iodine-131 tositumomab. Baseline patient characteristics (N = 14) were: median age, 52.5 years, > 60 years old (2 patients), male (7 patients), median time from diagnosis (2 months), and stage at time of treatment (stage II, 1 patient; stage IV, 13 patients).
Patients received a single dosimetric dose (450 mg of tositumomab intravenously [IV] followed by 35 mg [5 mCi] of iodine-131 tositumomab over 20 minutes) and then had three whole-body counts obtained over the next 7 days. The whole body counts were used to calculate the required activity (mCi) to deliver the desired therapeutic dose
(65 cGy for platelet counts of 100,000 to 149,000 cells/mm³ and 75 cGy for platelets ³ 150,000 cells/mm³). The single therapeutic dose (450 mg of tositumomab IV followed by 35 mg of tositumomab containing an appropriate amount of activity [mCi] of iodine-131 to deliver the specified total-body dose [cGy] over 20 minutes) was administered 7 to 14 days after the dosimetric dose.
The toxicity following fludarabine was mainly hematologic. The principal toxicity following iodine-131 tositumomab was also hematologic: absolute neutrophil count (ANC) was < 500 cells/mm³ in five patients (36%); platelet count was < 10,000 cells/mm³ in one patient (7%). Nonhematologic toxicity was typically mild to moderate; the most frequent events were nausea, asthenia, headache, increased cough, and rhinitis. One patient developed antimurine antibodies (HAMA).
An investigator-assessed response was seen in 13 of 14 patients (93%; 2 complete responses [CRs], 11 partial responses [PRs]) after fludarabine. At 25 weeks after treatment with iodine-131 tositumomab, 14 (100%) of 14 patients had achieved a response (10 CRs [71%], 4 PRs). Of the 11 PRs after fludarabine, 7 converted to CRs after iodine-131 tositumomab. One patient with stable disease after fludarabine converted to a CR. Three patients have developed progressive disease. Only one patient required a reduction in the fludarabine dosage.
CONCLUSIONS: Fludarabine, followed by tositumomab and iodine-131 tositumomab, can be safely administered to patients. The immunosuppressive effects of fludarabine limit the seroconversion to HAMA positivity in patients receiving tositumomab and iodine-131 tositumomab. The efficacy of tositumomab and iodine-131 tositumomab appears to augment that of fludarabine, improving overall responses and CRs. All treated and evaluated patients exhibited a response during the study. Additional patients have been treated and will be assessed.