Abstract

Conjugation of radionuclides to monoclonal antibodies provides a strategy to target radiation therapy directly to cells expressing the antigen of interest, also known as radio-immunotherapy (RIT). This modality has emerged as an effective targeted anti-neoplastic strategy in patients with B cell lymphoma. Certain hematologic malignancies express abnormally high levels of interleukin (IL)-2Rα (CD25, Tac) including cutaneous T cell lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, Hodgkin’s lymphoma (HL) and chronic lymphocytic leukemia. In this study 90Y-labeled daclizumab in CD25 positive malignancies, other than adult T cell leukemia, was investigated. We determined that 15 millicuries (mCi) was the maximum tolerated dose (MTD) in patients without a history of stem cell transplantation. As objective responses were only seen in HL, the phase II component of the study has focused on patients (pts) with relapsed and refractory HL. Eligibility criteria include: Karnofsky performance status (KPS) >50%, AGC >1,500/mm3, platelet >100,000/mm3, adequate hepatic/renal function and informed consent. As an added safety measure pts with a prior history of peripheral stem cell transplantation received an initial dose of 10mCi; in the absence of hematologic toxicity subsequent cycles were administered at 15mCi. All other pts received 15 mi 90Y-daclizumab every 6 weeks until disease progression, DLT or completion of 7 cycles. Ca-DTPA was used to reduce bone marrow exposure to free 90Y. 111In-labeled daclizumab was used for tumor imaging. Thirty pts with Hodgkin’s lymphoma have been treated, median age of 35 years (range, 20 to 67 years). The majority are heavily pre-treated, median of 4 prior chemotherapy regimens, range 1–8. Twenty pts had received a prior autologous transplantation; while 4 patients had received both autologous and allogeneic transplantation. One hundred cycles have been administered, median cycles per patient is 3 (range 1–7 cycles). Of 30 pts treated with 90Y-daclizumab, 12 achieved a complete response (CR), 7 had a partial response (PR), 5 had stable disease and 6 progressed. The response rate in pts who had undergone a transplant was 80%. Interestingly, many of the responses were seen in pts with CD25 negative malignant cells but with surrounding CD25 positive T cells within the tumor microenvironment. The median response duration was 129 days (range 28 to 720 days). The freedom from progression for the pts with a CR ranged from 28 to 788 days with a median of 222 days. There were no infusional reactions, however 5 pts developed non-symptomatic human anti-human antibody (HAHA) titers to daclizumab after one or more treatments. Seven pts failed to recover platelet count to the protocol mandated limit of 75,000, resulting in halting therapy, and 3 pts developed myelodysplastic syndrome (MDS) after 90Y-daclizumab, however one of those patients in retrospect had evidence of the same cytogenetic abnormalities predating therapy. 90Y-daclizumab produces objective responses in relapsed and refractory HL but as with other RIT strategies is not a curative approach. The role for 90Y-daclizumab in patients with relapsed HL with stem cell transplantation will be investigated.

Disclosures: Brechbiel:National Cancer Institute: Patents & Royalties. Waldmann:national Cancer Institute: Patents & Royalties.

Author notes

Corresponding author