Dose-attenuated radioimmunotherapy with tositumomab and iodine 131 tositumomab in patients with recurrent non-Hodgkin's lymphoma (NHL) and extensive bone marrow involvement.

Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor >25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of >25% and platelet count of >or=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count <500 cells/mm3 or platelets <25,000/mm3 for >17 days, or absolute neutrophil count <750/mm3 or platelets <50,000/mm3 for >24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with >25% BMI has acceptable toxicity and can result in lymphoma responses.

Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab. RESULTS: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT. CONCLUSION: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.

Subsequent therapy can be administered after tositumomab and iodine I-131 tositumomab for non-Hodgkin lymphoma.

BACKGROUND: Iodine I-131 tositumomab is a well tolerated and effective therapy for recurrent low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). Hematologic reserve after radioimmunotherapy (RIT) is an important consideration when subsequent therapy is required. METHODS: One hundred fifty-five patients who received treatment with I-131 tositumomab were assessed, and 68 patients had progressive disease after RIT. The median age (n=68 patients) was 59 years (range,18-82 yrs), and patients received a median of 2 pre-RIT regimens (range,1-8 regimens), including 66% who received anthracycline, 19% who received platinum, and 50% who received fludarabine. RESULTS: The median time to disease progression (among progressors) was 168 days (range, 19-771 days). At the time they developed recurrent disease, patients had median white blood cell count (WBC) of 4.9 K cells/microL (range, 1.1-21.4 K cells/microL), a median absolute neutrophil count (ANC) of 3.25 K cells/microL (range, 0.59-8.20 K cells/microL), a median platelet count of 130 K cells/microL (range, 9-440 K cells/microL), and there was no significant difference between pre-RIT and recurrence values except for the platelet count (P<0.05). No patient demonstrated a WBC<1.0 K cells/microL or an ANC<0.5 K cells/microL, although 1 patient had a platelet count<10 K cells/microL. Twenty-four patients subsequently received no further chemotherapy; and, in 21 patients (88%), hematologic parameters appeared to allow subsequent chemotherapy if necessary (blood counts: National Cancer Institute Grade 0-2). Among 44 patients (65%) who received further chemotherapy (median, 2 regimens; range, 1-4 regimens), 19 patients (43%) were treated with anthracyclines, 17 patients (39%) were treated with platinum, 10 patients (23%) were treated with fludarabine, and 13 patients (30%) underwent stem cell transplantation. Disease improvement occurred in most patients, although 18 patients died (40%) after further chemotherapy, predominantly from refractory lymphoma. CONCLUSIONS: Most patients with progressive disease after treatment with iodine I-131 tositumomab were able to receive subsequent therapy, including cytotoxic chemotherapy and stem cell transplantation.