Abstract

Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL at relapse or upon confirmation of refractory disease. Long-term responses in excess of 6 years have been observed following ibritumomab tiuxetan administration, underscoring the efficacy of this selective treatment modality. Dosing guidelines for 90Y ibritumomab tiuxetan were established in phase 1/2 trials and are dependent on body mass and platelet count, with the maximum recommended dose being 32 mCi. Biodistribution is evaluated by whole-body imaging prior to the delivery of the therapeutic dose using the gamma emitter indium 111 (111In) as the imaging radioimmunoconjugate. Current imaging methodology for the ibritumomab tiuxetan regimen has several limitations. First, the correlation between 111In ibritumomab tiuxetan dosimetry and either toxicity or tumor response is poor, and clinical parameters such as platelet count, patient weight, and percentage lymphomatous bone marrow involvement have been much more accurate. Further, while gamma (or PET/SPECT) imaging provides a visual evaluation of uptake in the blood pool and relevant organs, it cannot resolve biodistribution to the cellular level. This is particularly relevant for discriminating between radioisotope uptake in malignant and nonmalignant tissues. In order to assess the uniformity of cellular localization of 90Y ibritumomab tiuxetan, we performed autoradiographic analyses of lymph node tissue and bone marrow sampled after ibritumomab tiuxetan therapy. We also proposed to semi-quantify the energy doses delivered to lymphomatous tissue in an effort to better understand mechanisms of cellular sensitivity or resistance to this form of radioimmunotherapy. Following standard delivery of the ibritumomab tiuxetan regimen, bone marrow and lymph node tissues were sampled from a patient who presented with CD20+ NHL, bulky peripheral lymph nodes, and positive bone marrow involvement. Samples were collected 4 days after the administration of 90Y ibritumomab tiuxetan and immediately processed. Prepared sections were stained with hematoxylin and eosin (H&E) for histologic examination and then submitted for autoradiographic preparation with Kodak NBT-3 nuclear emulsion at 42o C, Kodak D-19 developer, and sodium thiosulphate fixative. Within lymph node tissue, radioisotope uptake was preferentially localized to lymphoma cells. An absence of significant localization in the histologically normal sections of bone marrow was also noted. The observed distribution patterns in the lymph node suggested that distribution of 90Y ibritumomab tiuxetan was localized to the cell membrane of lymphoma cells, with limited stromal and intravascular involvement. We are currently quantifying the density of radioisotope aggregation within malignant cells to assess whether a sufficient quantity of nuclide is recruited to achieve a crossfire effect on neighboring, unlabeled cells. Our results confirm that in vivo,90Y ibritumomab tiuxetan selectively targets tumor tissue with little binding to normal bone marrow and lymph node tissue, including stroma and vasculature. Additional patients with CD20+ NHL are being studied to verify the cellular localization pattern of 90Y ibritumomab tiuxetan.

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