Evaluating changes in stable chromosomal translocation frequency in patients receiving radioimmunotherapy

Purpose: The lack of any consistent correlation between radioimmunotherapy (RIT) dose and observed hematologic toxicity has made it difficult to valid ate RIT radiation dose estimates to marrow. Stable chromosomal translocatio ns (SCT) which result after radiation exposure may be a biologic parameter that more closely correlates with RIT radiation dose. Increases in the freq uency of SCT are observed after radiation exposure and are highly correlate d with absorbed radiation dose. SCT are cumulative after multiple radiation doses and conserved through an extended number of cell divisions. The purp ose of this study was to evaluate whether increases in SCT frequency were d electable in peripheral lymphocytes after RIT and whether the magnitude of these increases correlated with estimated radiation dose to marrow and whol e body. Methods and Materials: Patients entered in a Phase I dose escalation therap y trial each received 1-3 intravenous cycles of the radiolabeled anti-carci noembryonic antigen (CEA) monoclonal antibody, Y-90-chimeric T84.66, Five m Ci of In-111-chimeric T84.66 was co-administered for imaging and biodistrib ution purposes, Blood samples were collected immediately prior to the start of therapy and 5-6 weeks after each therapy cycle. Peripheral lymphocytes were harvested after 72 hours of phytohemagglutinin stimulation and metapha se spreads prepared. Spreads were then stained by fluorescence in situ hybr idization (FISH) using commercially available chromosome paint probes to ch romosomes 3 and 4, Approximately 1000 spreads were evaluated for each chrom osome sample. Red marrow radiation doses were estimated using the AAPM algo rithm and blood clearance curves. Results: Eighteen patients were 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 estimated marrow dos es ranged from 9.2 to 310 cGy, Increases in SCT frequencies were observed a fter each cycle for both chromosomes 3 and 4 in 16 of 18 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 obser ved between chromosomes 3 and 4, A linear correlation between cumulative ma rrow dose and increases in SCT frequencies was observed for chromosome 3 (R -2 = 0.63) and chromosome 4 (R-2 = 0.80), A linear correlation was also obs erved between increases in SCT frequency and whole body radiation dose or a dministered activity (R-2 = 0.67-0.89), There was less correlation between observed decrease in wbc or platelet counts and marrow dose, whole body dos e, or administered activity (R-2 = 0.28-0.43), Conclusions: Increases in SCT frequency were detectable in peripheral lymph ocytes after low dose-rate RIT irradiation. A linear correlation was observ ed between increases in SCT and marrow dose, whole body dose, and administe red activity. This correlation provides one of the strongest radiation dose -response and activity-response relationships observed with RIT, The detect ion of SCT mag therefore have application as an in situ integrating biodosi meter after RIT, This biologic parameter should prove useful in comparing e ffects on marrow for different therapeutic radionuclides and in comparing e ffects of RIT and external beam radiation doses on a cGy per cGy basis. As a result, this should allow for a more direct comparison between different methods of irradiation and in further refinement of radioimmunotherapy dose estimates and dosimetry methodology. (C) 2000 Elsevier Science Inc.