Tositumomab Effective for Untreated and Relapsed, Low-Grade and Follicular NHL

NEW ORLEANS-The monoclonal antibody tositumomab (Bexxar) showed promising efficacy in low-grade and follicular non-Hodgkin’s lymphoma in several preliminary studies reported during poster presentations at the ASH meeting.

Julie M. Vose, MD, of the University of Nebraska in Omaha reported that both naked tositumomab and tositumomab linked to iodine 131 are safe and effective for treating patients with low-grade follicular lymphoma. Dr. Vose analyzed data from five phase I/II studies including 179 patients with follicular small cleaved cell or follicular mixed cell with greater than 50% small cleaved cell histology at the time of treatment.

Infusions Well Tolerated

Most patients had received a single dosimetric dose of 450 mg of tositumomab IV over 1 hour followed by 35 mg of tositumomab radiolabeled with 5 mCi of iodine 131 over 12 hours. Whole-body gamma camera counts were then obtained over the next week. These 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 >150,000 cells/mm³). About 7 to 14 days after the dosimetric dose, patients received a single therapeutic dose of 450 mg of tositumomab followed by 35 mg of tositumomab containing an appropriate activity of iodine 131 to give the total body dose.

Dr. Vose reported that responses were observed in 145/179 (81%) of patients and that 69/179(39%) had complete responses (CR). The median duration of response was 11 months, and the mean duration of complete response was 57 months.

“Tositumomab and iodine-131 tositumomab produced an overall response in 74 patients with relapsed follicular small-cleaved and in 75% of patients with relapsed follicular mixed cell NHL,” Dr. Vose said. “Infusions were well tolerated, with infusion rate adjustments required in only 7% of the dosimetric infusions and 2% of the therapeutic dose infusions. Median hematologic toxicity nadirs occurred 32 to 45 days after therapy and were reversible. Overall, only 19% of patients required hematologic support.”

Previously untreated patients were more likely to develop human-anti-murine antibodies (HAMA). Dr. Vose said that only 11% of patients previously treated with chemotherapy developed HAMA.

 Used With Fludarabine

John P. Leonard, MD, of Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, reported preliminary data showing that fludarabine (Fludara) and iodine-131 tositumomab can be given safely as a combination regimen and that “the immunosuppressive effect of fludarabine appears to suppress HAMA response to tositumomab and I-131 tositumomab” in patients with previously untreated low-grade or follicular NHL.

This study involved 38 patients, including 14 evaluable for response at the time of this report. All patients received 3 cycles of fludarabine (25 mg/m² for 5 days every 5 weeks). Patients then received oral iodine for thyroid blockade and a single dosimetric dose of 450 mg of tositumomab IV over 1 hour followed by 35 mg (5 mCi) of I-131 tositumomab over 20 minutes.

Whole-body gamma counts were used to calculate the therapeutic dose, which was given 7 to 14 days after the dosimetric dose. Patients were given trimethoprim-sulfamethoxazole to prevent pneumocystis carinii pneumonia.

“The efficacy of tositumomab and I-131 tositumomab appears to augment that of fludarabine improving overall and complete responses, with 100% of patients achieving a response,” Dr. Leonard reported (see Table 1).

Only one patient developed HAMA, and the researchers concluded that the immunosuppressive effects of fludarabine limit seroconversion to HAMA. Toxicity following fludarabine was mainly hematologic. The principal toxicity following combination treatment was also hematologic, with 5/15 patients (36%) having an absolute neutrophil count (ANC) nadir of less than 500 cells/mm3 and 1/14 (7%) having a platelet nadir under 10,000 cells/mm³.

Relapsed or Refractory NHL

Stephanie A. Gregory, MD, of Rush Cancer Institute in Chicago reported preliminary data showing that tositumomab can be safely administered to patients with relapsed or refractory low-grade or transformed low-grade NHL who have been previously treated with rituximab (Rituxan). All 30 patients in an expanded access study had previously received rituximab. They were then treated with dosimetric and then therapeutic doses of tositumomab and iodine 131 tositumomab. Hematologic toxicities included ANC nadir less than 500 cells/mm³ in 5 (18%) patients, platelet nadir less than 10,000 cells/mm³ in 1 (4%), and hemoglobin nadir less than 6.5 g/dL in 1 (4%). One patient had febrile neutropenia possibly related to treatment.