Purpose/Objective: The lack of any consistent dose-response correlations after radioimmunotherapy (RIT) has prompted efforts to validate RIT dose estimates to tumor and normal organs. Increases in the frequency of stable chromosomal translocations (SCT) are observed after radiation exposure and are highly correlated with radiation dose. SCT are cumulative after multiple doses and conserved through an extended number of cell divisions and years of follow-up. The purpose of this study was to evaluate whether the detection and quantitation of changes in SCT frequency could be used as a biologic dosimeter after multi-cycle RIT, which could then be used to verify and refine RIT dose estimates and to establish more predictable dose-response relationships for more rational RIT treatment planning.Materials & Methods: Patients entered in a Phase I dose escalation therapy trial at this institution each received 1-3 cycles intravenously of the radiolabeled anti-CEA monoclonal antibody, 9 0 Y-chimeric T84.66, every 6 weeks. Five mCi of 1 1 1 In-chimeric T84.66 was co-administered for dosimetry purposes. Blood samples were collected immediately prior to and 6 weeks after each therapy cycle. Peripheral lymphocytes were collected after 72 hours of phytohemagglutanin stimulation and metaphase spreads prepared. Spreads were then stained by fluorescence in situ hybridization using commercially available chromosome paint probes to chromosomes 3 and 4. Approximately 1000 spreads were evaluated for each chromosome sample. Red marrow radiation doses were estimated using the AAPM algorithm and blood clearance curves.Results: Seventeen patients have been studied, each receiving at least one cycle of therapy ranging from 5-22 mCi/m 2 . Three patients received 2 cycles and two patients received 3 cycles of therapy. Cumulative marrow doses ranged from 9.2 to 310 cGy. Increases in SCT frequencies were observed after each cycle for both chromosomes 3 and 4 in 15 of 17 patients and in at least one chromosome for the remaining 2 patients. Cumulative increases in SCT frequencies ranged from 0.001 to 0.046 with no major differences observed between chromosomes 3 and 4. A linear correlation between cumulative marrow dose and cumulative increases in SCT frequencies for chromosome 3 (r = 0.74) and chromosome 4 (r = 0.89) was observed. The data indicate that for every 100 cGy delivered to marrow by 9 0 Y-cT84.66, SCT frequency will increase by approximately 0.011 for chromosome 3 and 0.014 for chromosome 4.Conclusions: Increases in SCT frequency are detectable in peripheral lymphocytes after low dose-rate irradiation delivered by RIT. These changes correlate with marrow dose estimates and therefore this parameter may have application as a biologic dosimeter after RIT. It may prove useful in validating and comparing different RIT dosimetry methodologies and in comparing biologic effects in marrow for different therapeutic radionuclides on a cGy per cGy basis.