⁹⁰Y Ibritumomab Tiuxetan and Rituximab for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Non-Hodgkin’s Lymphoma.

Approximately 60% of adult patients (pts) with diffuse large B cell lymphoma (DLBCL) will relapse after first line therapy. Second line chemotherapy has response rates of 45–66% with median response duration of 3 to 5 months.⁹⁰Y ibritumomab tiuxetan (⁹⁰Y-IT) is a murine IgG1 kappa antibody against CD20 linked with a beta-emitting isotope approved for use in relapsed indolent lymphoma. Maintenance rituximab (R) has been reported to increase response rates and prolong remission duration in some lymphomas. We performed a phase II multicenter clinical trial to examine the efficacy of ⁹⁰Y-IT induction followed by maintenance R in pts with DLBCL. Eligible pts had histologically confirmed CD20+ DLBCL according to WHO criteria. Pts had disease that was either relapsed or refractory to anthracycline-based chemotherapy or pts were intolerant of anthracycline-based chemotherapy. Adequate baseline hematologic and organ function was required. Pts were required to have <25% bone marrow involvement based on bilateral bone marrow aspirate and biopsy. Pts were required to have bidimensionally measurable disease by CT with at least one lesion measuring over 2.0 cm. Pts received R 250 mg/m² immediately followed by ¹¹¹In-ibritumomab tiuxetan. Scans were then performed at 24 and 48 hours to insure there was no altered biodistribution. On week 2 pts received a second infusion of R 250 mg/m² followed by 0.4 mCi/kg ⁹⁰Y-IT if baseline platelet count >150,000/mm³ or 0.3 mCi/kg ⁹⁰Y-IT if baseline platelet count 100,000 to 149,000/mm³, total dose not to exceed 32 mCi. Pts received R 375 mg/m² on weeks 3–6. Pts with multiple extranodal sites or prior bone marrow involvement received CNS prophylaxis with intrathecal methotrexate or cytarabine. Non-progressing pts received maintenance R 375 mg/m² weekly x 4 every 6 months x 4 or until progression. Toxicity analysis was planned after 15 pts were enrolled. Stopping rules were not met. As of 7/12/2006, 16 pts have been treated of a planned 40. Pts ranged in age from 45 to 95 with a median age of 77. Forty-four percent of patients had a secondary IPI score ≥ 3. The median number of prior regimens is 2 ranging from 1–5. The ⁹⁰Y–IT treatment regimen produced an overall response rate of 37.5% with 25% CR at 12 weeks. All pts with a CR had a secondary IPI of 1. All pts with PD had a secondary IPI ≥ 2. To date, the median EFS is 2.5 months with a median follow-up of 6.3 months. Among responding patients, the median EFS is not reached with a median follow-up of over 11 [5.7- 22.2] months. Five patients (31%) continue to be in remission greater than 6 months, and three patients (19%) remain in remission for 1 year. The most frequently observed grade 3 or 4 toxicity was hematologic. 55.5% of pts experienced grade 3 or 4 neutropenia. 66.7% of pts experienced grade 3 or 4 thrombocytopenia. The most frequent non-hematologic adverse event was hypotension experienced during the R infusion. The ⁹⁰Y-IT treatment regimen has an acceptable toxicity profile in pts with relapsed/refractory DLBCL. The two week outpatient ⁹⁰Y-IT infusion produces response rates and durations similar to that of more prolonged cytotoxic chemotherapy regimens.