Tositumomab Therapy Leads to Durable Responses in Lymphoma

PHILADELPHIA—Salvage therapy with the radiolabeled monoclonal antibody tositumomab (Bexxar) produced durable complete remissions in patients with multiply relapsed or refractory non-Hodgkin’s lymphoma (NHL) or transformed indolent lymphoma when used as second-line therapy, and first-line tositumomab produced 5-year progression-free survival of 58.9% in patients with advanced follicular lymphoma.

Mark S. Kaminski, MD, who led the group that did the three studies on which these conclusions are based, presented them as posters at the 44th Annual Meeting of the American Society of Hematology (ASH abstracts 1381, 1382, and 1384). Dr. Kaminski is in the Department of Hematology and Oncology at the University of Michigan Medical Center, Ann Arbor.

Dr. Kaminski told ONI, "Tositumo-mab works in patients who have had multiple treatments and are refractory to chemotherapy. We found higher re-sponses to tositumomab than to the last prior chemotherapy in resistant patients, which is quite unusual for second-line regimens. Tositumomab worked in patients with low-grade lymphomas as well as in those with transformed low-grade lymphomas."

He noted further that tositumomab "worked in patients who were refractory to rituximab [Rituxan] and produced durable responses that have continued now for at least 8 years in about 20% of patients, which is something we have not seen in this population with any other treatment except allogeneic transplant."

[As ONI went to press, the FDA’s Oncologic Drugs Advisory Board met to review Bexxar, and voted in support of the efficacy of Bexxar therapy in rituximab-refractory patients and chemotherapy-relapsed and refractory, low-grade NHL, with or without transformation. A full report will appear in next month’s issue of ONI.]

The follicular lymphoma study (abstract 1381) attracted the most attention at the meeting, perhaps because it moved tositumomab into the front-line setting. Responses to tositumomab salvage therapy for patients with chemotherapy-relapsed or refractory low-grade NHL have been well documented, and as Dr. Kaminski pointed out, treatments that are effective in relapsed or refractory disease are typically even more effective when used as initial therapy earlier in the disease course.

Determining Dose

The standard method for giving tositu-momab in all of these studies involves an initial "dose-metric dose" to determine dosage for the individual patient, then the therapeutic dose a week later. Thyroid protective agents are given beginning on day 1 and continuing until 14 days after the last therapeutic dose.

To establish dose, patients are given 450 mg of unlabeled tositumomab infused over 1 hour, then a 35-mg tracer dose of iodine-131-labeled tositumomab, infused over 20 minutes. Total body radiation counts are measured before treatment, then on days 2, 3, or 4, and finally on day 6 or 7. For therapeutic dosing, the patient is given 450 mg of unlabeled tositumomab followed by enough I-131-labeled tositumomab to deliver 75 cGy of total body irradiation, based on data from the dosimetric test.

Follicular Lymphoma

The phase II, single-center follicular lymphoma study enrolled 76 patients with previously untreated stage III/IV low-grade NHL. Of these, 69% had follicular small cell cleaved, 29% had follicular mixed cell, and 2% had mantle cell lymphomas. Two thirds of patients had bone marrow involvement, 31% had elevated baseline lactate dehydrogenase (LDH), and 43% had bulky disease (larger than 5 cm). Median age was 49 year (range, 23 to 66 years).

Of 76 patients, 72 (95%) had a confirmed response. "Median duration has not been reached, but responses continued at 5 years in 61% of patients. Of these, 57 (75%) had a confirmed complete response (CR), and 45 of these patients remain in CR at 30 to 66 months," Dr. Kaminski said. Five-year progression-free survival for all patients is 58.9% at a median follow-up of 49.3 months. Progression-free survival was significantly greater in patients who had a complete remission.

Grade 4 hematologic toxicity occurred in 5% of patients, but none required supportive care. No myelodysplastic syndromes had been seen at a median follow-up of 2.6 years; 7% of patients required thyroid supplementation.

Human antimouse antibodies (HAMA) against tositumomab were seen in 63% of patients. "This is significantly higher than observed in studies of previously treated patients, where the cumulative incidence is about 10%," Dr. Kaminski said. The development of HAMA has been a concern because of the possibility that such antibodies might reduce the efficacy of the therapeutic antibody, cause anaphylactic reactions, or lead to misleading results in immunoassays. Dr. Kaminski told ONI that such concerns now appear overblown in light of the durable CRs seen in patients in his studies and the relatively low toxicity.

"I would like to see a head-to-head randomized controlled trial of tositumo-mab vs a chemotherapy/rituximab regimen as front-line therapy," Dr. Kaminski commented.

Tositumomab produced a substantial number of durable complete responses in patients with relapsed or refractory low-grade NHL who had participated in five clinical trials that Dr. Kaminski retrospectively analyzed (abstract 1382). The data included 250 patients, of whom 33% were over age 60, two thirds had bulky disease, and 46% had bone marrow involvement. Patients had a median of four prior regimens, and 28% had transformed NHL. Seventy-nine percent had International Prognostic Index (IPI) scores of 2 or greater, and 72% were refractory to previous regimens.

Tositumomab produced an overall response rate of 56% in these multiply relapsed patients, with a median response duration of 13 months. Thirty percent of patients had a complete response, with a median duration of 58.4 months. "To date, 70% of the patients who achieved a CR are alive and remain in CR at up to 7.8+ years," Dr. Kaminski said.

Transformed Indolent Lymphomas

The third study in this group (abstract 1384) showed that tositumomab can produce durable responses (defined as time to progression of at least 12 months) in patients with transformed indolent lymphomas. Five patients in this study remain in remission beyond 40 months, and the longest is still in remission at 66 months after treatment.

"Histologic transformation of indolent lymphoma carries a poor prognosis. There are few treatment options for these patients, virtually all patients relapse and ultimately die either from lymphoma or from complications of treatment," Dr. Kaminski said.

In general, he noted, treatment of relapsed disease results in lower response rates and shorter duration of response with each successive treatment attempt. "To date, no single therapy has shown a consistent increase in durable response in patients with either recurrent or transformed low-grade NHL. A single administration of tositumomab showed significant efficacy and durable responses in patients with advanced-stage relapsed and refractory low-grade NHL," he said.

Median of Four Prior Therapies

This retrospective report included 71 patients with transformed low-grade NHL who had been enrolled on five tositumomab studies since 1990. Median age was 59 years, and median time from diagnosis to study entry was 74 months (range, 8 to 334 months). The median number of prior therapies was four. In addition to transformed histology, 28% of patients had bone marrow involvement, 70% had bulky disease, 57% had elevated LDH, and 52% had IPI scores of 3 or worse.

Median follow-up after a single administration of tositumomab was 19.4 months. Dr. Kaminski reported that the overall response rate was 39%, with a median duration of 21 months. A CR was achieved in 25% of patients, with a median duration of 36.5 months. As might be expected, median time to progression was much longer for patients who had a CR: 16.5 months vs 4.3 months for all patients.

An impressive point made in this poster was that CRs were observed among patients with all types of poor-prognostic factors, including 14% of patients with IPI of 3 or greater, 25% of patients with bone marrow involvement, and 24% of patients with four or more prior therapies. "These results demonstrate that tositumomab is an effective therapy for patients with transformed low-grade NHL," Dr. Kaminski said.