Ibritumomab tiuxetan (Zevalin) consists of an anti-CD20 murine IgG1 kappa monoclonal antibody covalently bound to tiuxetan (MX-DTPA), which stably chelates yttrium-90 for therapy. Ibritumomab tiuxetan therapy involves pretreatment with two doses of rituximab (Rituxan) at 250 mg/m2 1 week apart to clear peripheral blood of B cells and allow optimal targeting.
A total of 211 patients with relapsed or refractory low-grade, follicular, transformed, or intermediate-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated on four clinical trials: a phase I/II dose-finding trial, a phase II trial of reduced-dose ibritumomab tiuxetan (0.3 mCi/kg) in patients with mild thrombocytopenia, a phase III randomized trial of 0.4 mCi/kg, and a phase III nonrandomized trial of 0.4 mCi/kg in patients with rituximab-refractory follicular NHL. All patients had < 25% bone marrow involvement, circulating lymphocytes < 5,000/µL, absolute neutrophil count (ANC) > 1,500/µL, platelets > 100,000/µL, and no prior stem cell therapy. These patients represented a refractory population with advanced disease. Median age was 58 years (34% 65 years); 56% had tumors > 5 cm, 30% > 7 cm, and 11% > 10 cm; 13% had splenomegaly; 45% had bone marrow involvement; 16% were in the International Prognostic Index intermediate/high or high-risk group; there was a median of two prior therapies (range: 1 to 9 therapies); and 67% were resistant to any prior chemotherapy.
Toxicity was primarily hematologic, transient, and reversible. Median nadirs included ANC 800/µL, platelets 37,500/µL, and hemoglobin 10.3 g/dL. Grade 4 neutropenia and thrombocytopenia occurred in 32% and 8.5% of patients, respectively. Only 17% of patients used one or more hematopoietic growth factors; 18% and 22% of patients were transfused red cells and platelets, respectively. Prophylactic oral antibiotics were used in 10% of patients. Median serum immunoglobulin levels remained within the normal range, despite a 6-month reversible depletion of B cells.
There was no excessive infection risk, with only 7.6% of patients hospitalized with infections. Myelodysplasia or acute myelogenous leukemia was reported in 4 (1.9%) patients from 8 to 24 months after ibritumomab tiuxetan treatment, which is well within the 4% to 8% cumulative incidence reported for this heavily pretreated patient population. Most nonhematologic toxicity was related to rituximab infusions and was reversible. No liver or kidney function abnormalities were attributable to ibritumomab tiuxetan treatment. Three patients developed human antimouse antibody (1.4%) and one developed human antichimeric antibody (0.5%).
CONCLUSION: Ibritumomab tiuxetan therapy is very well tolerated, even in this refractory population at risk for toxicity.