Transformation of low-grade non-Hodgkins lymphoma (NHL) to a more aggressive histology is associated with a very poor response to chemotherapy and shortened survival. Therefore, new therapeutic agents are needed. Tositumomab/iodine-131 tositumomab (Bexxar) is a new radioimmunotherapy in development for the treatment of relapsed or refractory, low-grade or transformed, low-grade NHL.
Data from 49 patients with transformed, low-grade NHL from four phase I-III studies were analyzed. The patients were initially diagnosed with low-grade (small cell lymphocytic; follicular small cleaved cell; or follicular mixed cell, with > 50% small cleaved cell). Transformation required biopsy demonstration of a more aggressive histology at any time prior to study entry, and included diffuse large cell (27 patients), follicular large cell (12 patients), diffuse mixed cell (10 patients), large cell immunoblastic (2 patients), and other higher-grade histologies (8 patients).
Patients had received a median of 4 (range, 1 to 11) prior chemotherapy regimens, and 29 (49%) of 59 patients had not responded to their last chemotherapy regimen. Median duration of response to the last chemotherapy regimen was 4.2 months (range, 2.0 to 16.0 months). Median age was 59 years; 33 patients were male; median time from diagnosis to study entry was 80 months; 32 (56%) patients had elevated lactate dehydrogenase (LDH); and 17 (29%) patients had a positive baseline bone marrow biopsy (< 25% lymphoma involvement).
Patients generally received a single dosimetric dose (450 mg of intravenous ([IV] of tositumomab, followed by 35 mg of tositumomab radiolabeled with 5 mCi of iodine-131. Patients 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 platelets 100,000 to 149,999 cells/mm³ and 75 cGy for platelets ³ 150,000 cells/mm³). A single therapeutic dose (450 mg of tositumomab IV, followed by 35 mg of tositumomab containing an appropriate activity [mCi] of iodine-131 to deliver the specified total -body dose [cGy]) was administered 7 to 14 days after the dosimetric dose.
An investigator-assessed response was observed in 26 (53%) of 49 patients following iodine-131 tositumomab, and 16 (33%) patients achieved a complete response (CR). Median duration of response was 12.7 months (95% confidence interval [CI], 6.9 to 36.5 months). Median duration of CR was 36.5 months (95% CI, 14.3 to 36.5 months).
The principal toxicity was hematologic; absolute neutrophil count (ANC) was < 500 cells/mm³ in 19% of patients, and platelets were < 10,000 cells/mm³ in 4%. The nadir typically occurred at week 5 to 6, with recovery by week 8 to 9.
Transient, mild to moderate nonhematologic toxicities occurred, with the most frequent events being fever, fatigue, and nausea. Five patients developed human antimurine antibodies.
Median survival from study entry was 21.9 months (95% CI, 14.1 months to not reached).
CONCLUSION: These results demonstrate that iodine-131 tositumomab is a safe and effective therapy for the treatment of patients with transformed, low-grade NHL.