Ibritumomab tiuxetan (IDEC-Y2B8 [Zevalin]) is an anti-CD20 murine immunoglobulin G1 (IgG1) kappa monoclonal antibody conjugated to tiuxetan that can securely chelate either indium-111 (111In) for imaging/dosimetry or yttrium-90 (90Y) for therapy. Phase I/II trials (J Clin Oncol 17:3793-3803, 1999) demonstrated that the clinical parameters of baseline platelet count and percentage involvement of bone marrow with non-Hodgkins lymphoma (NHL) were correlated with the severity of hematologic toxicity, while bone marrow dosimetry was not. The maximum tolerated dose was found to be 0.4 mCi/kg (0.3 mCi/kg in patients with mild thrombocytopenia).
Based on these data, we conducted a phase II trial to further evaluate the safety and efficacy of 0.3 mCi/kg of 90Y-labeled tiuxetan for the treatment of patients with relapsed or refractory, low-grade, follicular, or transformed CD20-positive B-cell NHL. Patients with < 25% bone marrow involvement (on bone marrow biopsy), no prior radioimmunotherapy, circulating lymphocytes < 5,000 cells/mm³, an absolute neutrophil count (ANC) ³ 1,500 cells/mm³, platelet counts between 100,000 and 149,000 cells/mm³ and no prior autologous bone marrow transplantation (BMT) or stem-cell therapy were eligible. Accrual is now complete at 30 patients.
An interim analysis was performed on the first 24 patients. Their characteristics were: median age, 61 years (25% ³ 75 years); and 42% were female. A total of 83% of patients had follicular histology; 13%, transformed NHL; and 4%, small lymphocytic or lymphoplasmacytic NHL. Almost half of the patients (46%) had bulky disease ³ 5 cm; 21% had bulky disease > 7 cm; 13% had bulky disease ³ 10 cm; and 25% had splenomegaly. All 30 patients (100%) had received prior chemotherapy (median prior therapies, two); 13% had undergone prior radiotherapy; and 4% had received prior bioimmunotherapy.
All patients underwent imaging and dosimetry with 111In-labeled tiuxetan. In all cases, biodistribution and dosimetry were acceptable. (Protocol-defined limits for the estimated absorbed radiation dose were < 2,000 cGy to normal organs and < 300 cGy to bone marrow).
Toxicity was primarily hematologic, transient, and reversible. Median nadirs for patients receiving 0.3 mCi/kg (maximum dose, 32 mCi) were an ANC of 600 cells/mm³ platelets, 34,000 cells/mm³; and hemoglobin, 10.0 g/dL. Grade 4 neutropenia and thrombocytopenia occurred in 25% and 15% of these patients, respectively.
The overall response rate was 68% (23% complete responses [CRs]; 45% partial responses [PRs]) in the 22 patients for whom response assessment was available.
CONCLUSION: Patients with relapsed or refractory, low-grade, follicular, or transformed, CD20-positive B-cell NHL with mild thrombocytopenia can be safely treated with reduced-dose (0.3-mCi/kg) tiuxetan with an excellent clinical response.