Yttrium-90 Radiolabeled Daclizumab, An Anti-CD25 Monoclonal Antibody, Provides Effective Therapy for Refractory and Relapsed Hodgkin's Lymphoma,

Abstract 3706

Despite the success of treatment of patients with refractory and relapsed Hodgkin's lymphoma with combination chemotherapy, radiation and hematopoietic stem cell transplantation, a significant fraction of patients will not respond to treatment or will subsequently relapse and succumb to Hodgkin's lymphoma (HL). We have focused on CD25, the IL-2 receptor alpha subunit, as a target for systemic radioimmunotherapy of HL. The scientific basis for this choice is that with the exception of T regs, CD25 is not expressed by normal resting lymphoid cells whereas it is expressed on both a minority of Reed-Sternberg cells and also on regulatory T cells rosetting around the Reed-Sternberg cells. We have utilized the humanized monoclonal antibody, daclizumab that targets CD25 (IL-2R alpha) armed with yttrium-90 a radionuclide that provides strong beta emissions that kill tumor cells at a distance via a crossfire effect. Patients with histologically confirmed HL and expression of CD25 in at least 10% of the cells in the lymphomatous mass were eligible. Thirty consecutive patients with HL were entered. The patients had received a median of 4 prior chemotherapy regimens and were required to have had an autologous and/or allogeneic stem cell transplant or had refused a transplant. Patients were treated with an initial dose of 10 or 15 mCi of ⁹⁰Y-daclizumab depending on transplant status.

After the first cycle, patients could receive ⁹⁰Y-daclizumab 15 mCi per cycle every 6 to 10 weeks to complete up to a maximum of 7 doses if tolerated. A total of 98 cycles of treatment were administered to 30 patients with a median aggregate radiation dose of 40 mCi. In 30 HL patients treated with ⁹⁰Y-daclizumab there were 7 partial responses and 12 complete responses. Toxicities were limited to transient bone marrow suppression and the myelodysplastic syndrome (3 cases). Responses were seen among the 5 patients whose Reed-Sternberg cells expressed CD25 as well as in those whose neoplastic cells were CD25 negative provided that the associated rosetting T regs expressed CD25. The increased efficacy compared to alternative radioimmunotherapy strategies for HL appears to reflect the increase in the target antigen, CD25, in lymphomatous masses provided by the overexpression of CD25 by associated rosetting T cells, and the use of a high energy, beta-emitting radionuclide Yttrium-90 to arm the antibody that thereby does not have to come in contact with each tumor cell but can kill cells by crossfire at a distance.

In conclusion, repeated ⁹⁰Y-daclizumab infusions predominantly directed toward non-malignant T cells rosetting around Reed-Sternberg cells provided effective therapy for select HL patients.