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Phase I/II study of Yttrium-90 labeled humanized anti-Tac (HAT) monoclonal antibody and calcium DTPA in CD25-expressing malignancies

¹ Metabolism Branch, NCI, Bethesda, Maryland ² Nuclear Medicine, NIH, Bethesda, Maryland ³ Clinical Pathology, NIH, Bethesda, Maryland ⁴ Dept of Laboratory Medicine, NIH, Bethesda, Maryland ⁵ Radiation Oncology, NIH, Bethesda, Maryland

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Objectives: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and clinical response of 90Y-HAT in patients with CD25-expressing lymphoid malignancies other than ATL.

Methods: Eligibility: Patients (Pts.) with T cell malignancies and Hodgkin’s disease, CD25 staining 10% of malignant cells, KPS >50%, AGC >1,500/mm3, platelet >100,000/mm3, adequate hepatic/renal function and informed consent. Phase I dose escalation, started at 15mCi 90Y-HAT, and escalated by 5 mCi until DLT. In an attempt to reduce bone marrow exposure to free 90Y, Ca-DTPA was given. 111In-labeled HAT was used for tumor imaging. Patients received 90Y-HAT every 6 weeks until disease progression, DLT or completion of 7 cycles.

Results: Twenty three patients (Pts.), 8 with cutaneous T cell lymphoma (CTCL), 2 with peripheral T cell lymphoma (PTCL), 2 with anaplastic large cell lymphoma (ALCL), 10 with Hodgkin’s disease (HD) and 1 with chronic lymphocytic leukemia, median age 54 yrs (range, 24-75), median Karnofsky performance status (KPS) 90% (range, 50-90%), all with advanced disease with multiple prior therapies (median 4; range, 1-10) received 90Y-HAT every 6-10 weeks. Overall, 38 cycles were administered median 1 (range, 1-6). The single MTD was 15 mCi, with dose limiting thrombocytopenia in 2 of 3 Pts. treated with 20mCi of 90Y-HAT. Of 23 Pts., 5 (22%) had grade 3/4 thrombocytopenia, 4 (17%) had grade 3/4 anemia and 5 (22%) experienced grade 3/4 granulocytopenia. Tumor imaging by 111In-HAT was observed and confirmed by FDG-PET imaging when available. 111In-HAT distribution was similar to that of FDG, indicating localization of the radiolabeled antibody at the sites of disease. 111In-HAT and 90Y-HAT blood pharmacokinetics were similar although urinary excretion of 111In was greater than 90Y. Median overall survival is estimated at 5 months (range, 2-63). Objective responses have only been seen in the HD Pts. Of 10 HD pts there were 2 CRs, (9 and 1+ months), 2 PRs, 4SD, 1PD and one Pt is too early to assess. Although cumulative doses of 45 mCi of 90Y-HAT produced dose-limiting myelosuppression in a similar trial in Pts with HTLV-1-associated adult T cell leukemia/lymphoma, 2 HD Pts. tolerated doses of 90 and 60 mCi without myelosuppression.

Conclusions: We continue to enroll patients to the study, in particular those with Hodgkin’s disease as they may represent a particularly favorable group to target with 90Y-HAT radioimmunotherapy.

Research Support (if any): This research was supported in part by the Intramural Research Program of the NIH