Phase I/II 90 Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) radioimmunotherapy dosimetry results in relapsed or refractory non-Hodgkin's lymphoma

Abstract

Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

Time dependence of the activity concentration ratio of red marrow to blood and implications for red marrow dosimetry

“…The activity uptake in bone marrow changes with the anatomic location, 1 and this is especially the case if a region has previously been treated with external radiation therapy. When the exposed bone marrow volume is relatively small (Յ 25%), the bone marrow often fails to regenerate the ablated portion, since the compensatory process is able to meet the demands for the hematopoesis.…”

“…The hematologic toxicity is due to the energy deposited in the bone marrow, but the absorbed dose calculated with contemporary methods is not sufficient for adequate prediction of the toxicity. The usefulness of dosimetry has therefore been questioned, 1 and RIT has consequently been administered without preceding dosimetry. Although RIT can be administered without it, dosimetry should be used in order to optimize this treatment modality.…”

Radioimmunotherapy of non-Hodgkin lymphomas

“…Baseline bone marrow involvement and platelet counts have been shown to be accurate predictors of hematologic toxicity. 16,17 Instead, 2 imaging studies to determine favorable biodistribution are currently required to ensure tumor targeting and to ensure that safe doses of radiation are delivered to normal organs.…”

A Method to Correct for Radioactivity in Large Vessels That Overlap the Spine in Imaging-Based Marrow Dosimetry of Lumbar Vertebrae

“…These patients were selected to span the wide range of blood clearance times observed with various radiopharmaceuticals to assess the impact of radioactivity in blood vessels on image quantification of lumbar vertebral marrow. Although 111 In-B9E9 pretarget (14) and 131 I-HuCC49DCh2 (13) patients had relatively fast blood clearance and were expected to have less background contribution to marrow image quantification, 111 In-ibritumomab tiuxetan (12) and 111 In-CC49 (15) patients had slower blood clearance and were expected to have more background contribution to marrow image quantification. The patient selection criteria included abdominal CT images that covered lumbar vertebrae L2 through L4 for vessel volume measurement, serial blood samples that allowed determination of radioactivity in blood vessels, and a relatively wide range of patient body size.…”

“…The details of the radiopharmaceuticals and their administration have previously been reported (12)(13)(14)(15). These patients were selected to span the wide range of blood clearance times observed with various radiopharmaceuticals to assess the impact of radioactivity in blood vessels on image quantification of lumbar vertebral marrow.…”